Piperazine derivatives

ABSTRACT

The present invention relates to compounds of formula (I)  
                 
 
     as well as pharmaceutically acceptable salts, solvates and esters thereof. These compounds can be used to prepare pharmaceutical compositions for the treatment or prevention of disorders of the central nervous system, damage to the central nervous system, cardiovascular disorders, gastrointestinal disorders, diabetes, obesity and sleep apnoea.

FIELD OF THE INVENTION

[0001] The present invention relates to new piperazine derivatives, toprocesses and intermediates for their preparation, and to pharmaceuticalcompositions containing them. These compounds are useful in treatingobesity and other disorders mediated by 5HT₂ receptors.

BACKGROUND OF THE INVENTION

[0002] It has been recognised that obesity is a disease processinfluenced by environmental factors in which the traditional weight lossmethods of dieting and exercise need to be supplemented by therapeuticproducts (S. Parker, “Obesity: Trends and Treatments”, Scrip Reports,PJB Publications Ltd, 1996).

[0003] Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m², and obesity as a BMI greaterthan 30 kg/m². There are problems with this definition in that it doesnot take into account the proportion of body mass that is muscle inrelation to fat (adipose tissue). To account for this, obesity can alsobe defined on the basis of body fat content: greater than 25% and 30% inmales and females, respectively.

[0004] As the BMI increases there is an increased risk of death from avariety of causes that is independent of other risk factors. The mostcommon diseases with obesity are cardiovascular disease (particularlyhypertension), diabetes (obesity aggravates the development ofdiabetes), gall bladder disease (particularly cancer) and diseases ofreproduction. Research has shown that even a modest reduction in bodyweight can correspond to a significant reduction in the risk ofdeveloping coronary heart disease.

[0005] Compounds marketed as anti-obesity agents include Orlistat(XENICAL®) and Sibutramine. Orlistat (a lipase inhibitor) inhibits fatabsorption directly and tends to produce a high incidence of unpleasant(though relatively harmless) side-effects such as diarrhoea. Sibutramine(a mixed 5-HT/noradrenaline reuptake inhibitor) can increase bloodpressure and heart rate in some patients. The serotoninreleaser/reuptake inhibitors fenfluramine (Pondimin®) anddexfenfluramine (Redux™) have been reported to decrease food intake andbody weight over a prolonged period (greater than 6 months). However,both products were withdrawn after reports of preliminary evidence ofheart valve abnormalities associated with their use. There is thereforea need for the development of a safer anti-obesity agent.

[0006] Diabetes is a disease in which a patient's ability to controlglucose levels in blood is impaired, because the ability to respondproperly to the action of insulin has been partially lost. In type IIdiabetes, often referred to as non-insulin dependent diabetes mellitus(NIDDM), which afflicts 80-90 % of all diabetic patients in developedcountries, the Islets of Langerhans in the pancreas still produceinsulin. However, the target organs, mainly muscle, liver and adiposetissue, exhibit a profound resistance to insulin stimulation, thus thebody compensates by producing abnormally high levels of insulin. In thelater stages of the disease, however, insulin secretion decreases due topancreas exhaustion.

[0007] Current first line treatment for diabetes generally involvesadoption of a diet low in fat and glucose and taking regular exercise.However, compliance can be moderate and as the disease progresses,treatment with hypoglycemic drugs, e.g. sulfonylureas or metformin,becomes necessary. A promising new class of drugs has recently beenintroduced that resensitize patients to their own insulin (insulinsensitizers), thereby reverting blood glucose and triglyceride levels tonormal, and thus abolishing, or at least reducing, the requirement forexogenous insulin. Troglitazone (Resulin™) and rosiglitazone (Avandia™)belong to the thiazolidinediones (TZD) class of PPARγ-agonists and werethe first representatives of the class approved for NIDDM treatment inseveral countries. These compounds, however, suffer from side effectsincluding rare but severe liver toxicity (as seen with troglitazone),and increased body weight in humans. Therefore, new, better and moreefficacious drugs for the treatment of conditions involvinghyperglycaemia, particularly NIDDM are urgently needed. Recent studiesprovided evidence that coagonism of PPARα and PPARγ would result incompounds with enhanced therapeutic potential, i.e. with an improvedlipid profile effect on top of the normalization of glucose- andinsulin-levels (Keller and Wahli: Trends Endocrin. Metab. 1993; 4:291-296, Macdonald and Lane: Current Biology Vol. 5 pp. 618-621 (1995)).

SUMMARY OF THE INVENTION

[0008] It is an object of this invention to provide selective, directlyacting 5HT₂ receptor ligands for use in therapy and particularly for useas anti-obesity agents. It is a further object of this invention toprovide directly acting ligands selective for 5-HT_(2B) and/or 5-HT_(2C)receptors, for use in therapy and particularly for use as anti-obesityagents. It is a further object of this invention to provide selective,directly acting 5-HT_(2C) receptor ligands, preferably 5-HT_(2C)receptor agonists, for use in therapy and particularly for use asanti-obesity agents.

[0009] The compounds of this invention are either 5HT₂ receptor agonistsor antagonists. A skilled artisan can readily ascertain by conventionalassays which compounds are antagonists and which are agonists (see e.g.Eur. J. Pharmacol. Jul. 20, 2001; 424(2):85-90; Psychopharmacol. Bull.1989; 25(3):393-7). Preferably, these compounds are agonists.

[0010] In one embodiment, the invention relates to compounds of formulaI and their pharmaceutically acceptable salts, solvates and esters

[0011] wherein

[0012] R¹ is hydrogen, halogen, alkyl, cycloalkyl, alkenyl,alkoxycarbonylalkenyl, alkoxy, alkoxyalkyl, arylalkoxy, hydroxyalkyl,cyano, cycloalkylalkoxyalkyl, alkoxyalkoxyalkyl, arylalkoxyalkyl, amino,haloalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl,alkylcarbonyl, haloalkylcarbonyl, alkyl-S-, alkenyl-S-, A¹ or A²;

[0013] R² is hydrogen, alkyl or alkoxy;

[0014] R³ is alkyl, hydroxyalkyl or alkoxyalkyl;

[0015] R⁴ is hydrogen or alkyl;

[0016] A¹ is

[0017] R^(a) is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl;

[0018] R^(b) is hydrogen or alkyl; or R^(a) and R^(b) together with theoxygen atom and the carbon atom to which they are attached formtetrahydrofuranyl;

[0019] R^(C) is haloalkyl, alkyl, alkoxyalkyl or thiazolyl;

[0020] A² is

[0021] R^(d) is alkyl, cycloalkyl, aryl, aralkyl or alkenyl;

[0022] R^(e) is hydrogen or alkyl; or R^(d) and R^(e) together with thenitrogen atom to which they are attached form pyrrolidinyl orbenzyloxycarbonylpiperazinyl;

[0023] R^(f) is hydrogen or alkyl; and

[0024] R^(g) is hydrogen or alkyl.

[0025] The compounds of formula (I) are useful in the treatment and/orprevention of disorders involving elevated plasma blood glucose,particularly diabetes mellitus (including Type II or non-insulindependent diabetes mellitus (NIDDM); Type I or insulin dependentdiabetes mellitus (IDDM); and Type III or malnutrition-relateddiabetes). The diabetes may be diabetes secondary to pancreatic disease;or diabetes related to steroid use. The compounds of formula (I) arealso useful in the treatment and/or prevention of the sequelae ofhyperglycaemia; in the treatment and/or prevention of diabeticcomplications; and in the treatment of insulin dependence.

[0026] The invention is of particular use in the treatment or preventionof diabetes mellitus (including Type II or non-insulin dependentdiabetes mellitus (NIDDM); Type I or insulin dependent diabetes mellitus(IDDM); and Type III or malnutrition-related diabetes), and particularlyin the treatment or prevention of Type II diabetes.

[0027] In another embodiment, the present invention relates to a methodof acute and/or chronic treatment and/or prevention of disordersinvolving elevated plasma blood glucose, particularly the acute and/orchronic treatment of disorders involving elevated plasma blood glucose,and especially acute treatment of disorders involving elevated plasmablood glucose.

DETAILED DESCRIPTION OF THE INVENTION

[0028] As used herein, the term “alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 8carbon atoms, preferably a straight or branched-chain alkyl group with1-4 carbon atoms. Examples of straight-chain and branched C₁-C₈ alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, the isomeric pentyls, the isomeric hexyls, the isomericheptyls and the isomeric octyls, preferably methyl, ethyl, propyl andisopropyl. Particularly preferred are methyl and ethyl.

[0029] The term “cycloalkyl”, alone or in combination, signifies acycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkylring with 3 to 6 carbon atoms. Examples of C₃-C₈ cycloalkyl arecyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl,methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl,methylcyclohexyl, dimethyl-cyclohexyl, cycloheptyl and cyclooctyl,preferably cyclopropyl and cyclopentyl and particularly cyclopropyl.

[0030] The term “alkoxy”, alone or in combination, signifies a group ofthe formula alkyl-O- in which the term “alkyl” has the previously givensignificance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy and ethoxy.

[0031] The term “haloalkyl”, alone or in combination, signifies an alkylgroup as previously defined, wherein one or several hydrogen atoms,preferably one to three hydrogen atoms have/has been replaced byhalogen. Examples of haloalkyl groups are trifluoromethyl,trifluoroethyl, pentafluoroethyl and trichloromethyl. Preferred examplesare monofluoromethyl, trifluoromethyl and difluoromethyl. Particularlypreferred is trifluoromethyl.

[0032] The term “carbonyl” refers to a group of the formula —C(O)—.

[0033] The term “aryl”, alone or in combination, signifies a phenyl ornaphthyl group which optionally carries one to three substituents eachindependently selected from alkyl, alkoxy, halogen, carboxy,alkoxycarbonyl, aminocarbonyl, hydroxy, amino, nitro and the like, suchas phenyl, p-tolyl, 4-methoxyphenyl, 4-tert-butoxyphenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-hydroxyphenyl, 1-naphthyl and 2-naphthyl. Preferred are phenyl,4-fluorophenyl, 1-naphthyl and 2-naphthyl and particularly phenyl.

[0034] The term “aralkyl”, alone or in combination, signifies an alkylor cycloalkyl group, preferably an alkyl group as previously defined inwhich one or several, preferably one hydrogen atom has been replaced byan aryl group as defined before. Preferred is benzyl.

[0035] The term “amino”, alone or in combination, signifies a primary,secondary or tertiary amino group bonded via the nitrogen atom, with thesecondary amino group carrying an alkyl or cycloalkyl substituent andthe tertiary amino group carrying two similar or different alkyl orcycloalkyl substituents or the two nitrogen substituents togetherforming a ring, such as, for example, —NH₂, methylamino, ethylamino,dimethylamino, diethylamino, methyl-ethylamino, morpholin-1-yl,pyrrolidin-1-yl or piperidinyl etc., preferably amino, dimethylamino anddiethylamino and particularly primary amino.

[0036] The term “halogen” signifies fluorine, chlorine, bromine oriodine and preferably fluorine, chlorine or bromine and particularlychlorine and bromine.

[0037] The term “carboxy”, alone or in combination, signifies a —COOHgroup.

[0038] The term “alkenyl” alone or in combination signifies astraight-chain or branched-chain hydrocarbon group comprising a carboncarbon double bond and 1 to 10, preferably 1 to 8 carbon atoms, morepreferably 1-4 carbon atoms. Preferred examples are ethenyl and allyl.

[0039] The term “cyano”, alone or in combination, signifies a —CN group.

[0040] The term “pharmaceutically acceptable salts” refers to thosesalts which retain the biological effectiveness and properties of thefree bases or free acids, which are not biologically or otherwiseundesirable. The salts are formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, preferably hydrochloric acid, and organicacids such as acetic acid, propionic acid, glycolic acid, pyruvic acid,oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcystein and the like. In addition these saltsmay be prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from an inorganic base include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium, magnesiumsalts and the like. Salts derived from organic bases include, but arenot limited to salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymineresins and the like. The compound of formula I can also be present inthe form of zwitterions.

[0041] The invention expressly includes pharmaceutically usable solvatesof compounds according to formula I. The compounds of formula I can besolvated, e.g. hydrated. The solvation can be effected in the course ofthe manufacturing process or can take place, e.g. as a consequence ofhygroscopic properties of an initially anhydrous compound of formula I(hydration). The term pharmaceutically acceptable salts also includesphysiologically usable solvates.

[0042] “Pharmaceutically acceptable esters” means that compounds ofgeneral formula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

[0043] In more detail, for example, the COOH groups of compoundsaccording to formula I can be esterified. The alkyl and aralkyl estersare examples of suitable esters. The methyl, ethyl, propyl, butyl andbenzyl esters are preferred esters. The methyl and ethyl esters areespecially preferred. Further examples of pharmaceutically usable estersare compounds of formula I, wherein the hydroxy groups can beesterified. Examples of such esters are formate, acetate, propionate,butyrate, isobutyrate, valerate, 2-methylbutyrate, isovalerate andN,N-dimethylaminoacetate. Preferred esters are acetate andN,N-dimethylaminoacetate.

[0044] The term “lipase inhibitor” refers to compounds which are capableof inhibiting the action of lipases, for example gastric and pancreaticlipases. For example orlistat and lipstatin as described in U.S. Pat.No. 4,598,089 are potent inhibitor of lipases. Lipstatin is a naturalproduct of microbial origin, and orlistat is the result of ahydrogenation of lipstatin. Other lipase inhibitors include a class ofcompound commonly referred to as panclicins. Panclicins are analogues oforlistat (Mutoh et al, 1994). The term “lipase inhibitor” refers also topolymer bound lipase inhibitors for example described in InternationalPatent Application WO99/34786 (Geltex Pharmaceuticals Inc.). Thesepolymers are characterized in that they have been substituted with oneor more groups that inhibit lipases. The term “lipase inhibitor” alsocomprises pharmaceutically acceptable salts of these compounds. The term“lipase inhibitor” preferably refers to orlistat.

[0045] Orlistat is a known compound useful for the control or preventionof obesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul.1, 1986, which also discloses processes for making orlistat and U.S.Pat. No.6,004,996, which discloses appropriate pharmaceuticalcompositions. Further suitable pharmaceutical compositions are describedfor example in International Patent Applications WO 00/09122 and WO00/09123. Additional processes for the preparation of orlistat aredisclosed in European Patent Applications Publication Nos. 185,359,189,577, 443,449, and 524,495.

[0046] Orlistat is preferably orally administered from 60 to 720 mg perday in divided doses two to three times per day. Preferred is whereinfrom 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitoris administered to a subject, preferably in divided doses two or,particularly, three times per day. The subject is preferably an obese oroverweight human, i.e. a human with a body mass index of 25 or greater.Generally, it is preferred that the lipase inhibitor be administeredwithin about one or two hours of ingestion of a meal containing fat.Generally, for administering a lipase inhibitor as defined above it ispreferred that treatment be administered to a human who has a strongfamily history of obesity and has obtained a body mass index of 25 orgreater.

[0047] Orlistat can be administered to humans in conventional oralcompositions, such as, tablets, coated tablets, hard and soft gelatincapsules, emulsions or suspensions. Examples of carriers which can beused for tablets, coated tablets, dragées and hard gelatin capsules arelactose, other sugars and sugar alcohols like sorbitol, mannitol,maltodextrin, or other fillers; surfactants like sodium lauryl sulfate,Brij 96, or Tween 80; disintegrants like sodium starch glycolate, maizestarch or derivatives thereof; polymers like povidone, crospovidone;talc; stearic acid or its salts and the like. Suitable carriers for softgelatin capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Moreover, the pharmaceuticalpreparations can contain preserving agents, solubilizers, stabilizingagents, wetting agents, emulsifying agents, sweetening agents, coloringagents, flavoring agents, salts for varying the osmotic pressure,buffers, coating agents and antioxidants. They can also contain stillother therapeutically valuable substances. The formulations mayconveniently be presented in unit dosage form and may be prepared by anymethods known in the pharmaceutical art. Preferably, orlistat isadministered according to the formulation shown in the Examples and inU.S. Pat. No. 6,004,996, respectively.

[0048] In the nomenclature used in the present application the carbonatoms of the basic ring system of the compounds according to formula Iare numbered as follows:

[0049] wherein R¹ is attached to the 6-position, R² is attached to the9-position and R³ is attached to the 4-position.

[0050] Preferred compounds of formula I, and their pharmaceuticallyacceptable salts, solvates and esters, are compounds

[0051] wherein

[0052] R¹ is hydrogen, halogen, alkyl, cycloalkyl, alkenyl,alkoxycarbonylalkenyl, alkoxy, alkoxyalkyl, arylalkoxy, hydroxyalkyl,cyano, cycloalkylalkoxyalkyl, alkoxyalkoxyalkyl, arylalkoxyalkyl, aminoor haloalkyl;

[0053] R² is hydrogen, alkyl or alkoxy;

[0054] R³ is alkyl, hydroxyalkyl or alkoxyalkyl; and

[0055] R⁴ is hydrogen or alkyl.

[0056] The dotted lines in formula I (marked as *) represent a single ora double bond

[0057] Accordingly, compounds of formula (I) are of one of the followingformulae (Ia) and (Ib)

[0058] wherein R¹ to R⁴ are defined as before.

[0059] Preferred compounds of formula I are those which are of formulaIb. Particularly preferred are compounds of formula I which are offormula Ia.

[0060] The compounds of formula I can contain several asymmetric centresand can be present in the form of optically pure enantiomers, mixturesof enantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral absorbens or eluant).

[0061] The term “asymmetric carbon atom (C*) means a carbon atom withfour different substituents. According to theCahn-Ingold-Prelog-Convention the asymmetric carbon atom can be of the“R” or “S” configuration.

[0062] Preferred are chiral compounds of formula (Ia), wherein thecarbon atom number 9a has the R configuration.

[0063] Also preferred are chiral compounds of formula (Ic),

[0064] wherein R¹ to R⁴ are defined as before. Formula (Ic) means thatthe asymmetric carbon atom C*

[0065] is of the R configuration and R¹ to R⁴ are defined above,provided, however, that if R³ is alkoxymethyl, preferably hydroxymethyl,then C* is of the S configuration. The R³ substituent occupies anequivalent stereochemical position in the 3-dimensional space.

[0066] Further preferred compounds of formula (I) are those, wherein C*is of the R configuration and wherein R³ means alkyl.

[0067] Further preferred are those compounds according to formula (I),wherein C* is of the S configuration and R³ means alkoxymethyl, mostpreferably hydroxymethyl.

[0068] One preferred embodiment relates to the pharmaceuticallyacceptable salts of compounds of formula I. Preferred salts or compoundsof formula I are the hydrochloride salts.

[0069] Additionally preferred compounds according to formula I arethose, wherein R² is hydrogen or alkyl. Particularly preferred arecompounds of formula I, wherein R² is hydrogen. Further particularlypreferred are those compounds of formula I, wherein R² is methyl.

[0070] Further preferred are compounds of formula I, wherein R³ isalkyl, particularly methyl.

[0071] Moreover, preferred are compounds according to formula I, whereinR⁴ is hydrogen.

[0072] Preferred are compounds according to formula I, wherein R¹ ishydrogen, halogen, alkyl, cycloalkyl, alkoxycarbonylalkenyl,alkoxyalkyl, cyano, cycloalkylalkoxyalkyl, alkoxyalkoxyalkyl, amino orhaloalkyl.

[0073] A further preferred aspect of the present invention are compoundsof formula I, wherein R¹ is halogen, alkyl, cycloalkyl, alkenyl,alkoxycarbonylalkenyl, alkoxy, alkoxyalkyl, arylalkoxy, hydroxyalkyl,cyano, cycloalkylalkoxyalkyl, alkoxyalkoxyalkyl, arylalkoxyalkyl, aminoor haloalkyl.

[0074] Preferred are compounds of formula I, wherein R¹ is hydrogen,chloro, bromo, methyl, ethyl, trifluoromethyl, cyclopropyl,ethoxycarbonylethenyl, methoxypropyl, cyano, cyclopropylmethoxymethyl,methoxyethoxymethyl, methoxymethyl or primary amino.

[0075] Further preferred are compounds of formula I, wherein R¹ ischloro, bromo, methyl, ethyl, trifluoromethyl, cyclopropyl,ethoxycarbonylethenyl, methoxypropyl, cyano, cyclopropylmethoxymethyl,methoxyethoxymethyl, methoxymethyl or primary amino.

[0076] Also preferred are compounds of formula I, wherein R¹ ishydroxyalkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl, alkylcarbonyl,haloalkylcarbonyl, alkyl-S-, alkenyl-S-, A¹ or A².

[0077] Particularly preferred are those compounds of formula I, whereinR¹ is fluoromethyl, difluoromethyl, hydroxy-ethyl, methoxyethyl,ethoxyethyl, cyclopropylmethoxy-ethyl or allyl-S-.

[0078] Further preferred are compounds of formula I, wherein R¹ ishydrogen, halogen, alkyl, cycloalkyl, alkenyl, alkoxycarbonylalkenyl,alkoxy, alkoxyalkyl, arylalkoxy, hydroxyalkyl, cyano,cycloalkylalkoxyalkyl, alkoxyalkoxyalkyl, arylalkoxyalkyl, amino,haloalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl,alkylcarbonyl, haloalkylcarbonyl, alkyl-S- or alkenyl-S-.

[0079] Further preferred are compounds of formula I, wherein R¹ is A¹and particularly, wherein R^(a) is hydrogen, alkyl, cycloalkyl orcycloalkylalkyl; R^(b) is hydrogen or alkyl; and R^(C) is haloalkyl,alkyl, alkoxyalkyl or thiazolyl.

[0080] Also preferred are compounds of formula I, wherein R^(a) ishydrogen or methyl.

[0081] Further preferred are compounds of formula I, wherein R^(b) ishydrogen or alkyl.

[0082] Another preferred aspect of the invention are compounds offormula I, wherein R^(c) is trifluoromethyl or methyl.

[0083] Also preferred are those compounds of formula I, wherein R¹ is A²and particularly, wherein R^(d) is alkyl, cycloalkyl, aryl, aralkyl oralkenyl; R^(e) is hydrogen or alkyl; R^(f) is hydrogen or alkyl; andR^(g) is hydrogen or alkyl.

[0084] Preferred are those compounds of formula I, wherein R^(f) andR^(g) are hydrogen.

[0085] Also preferred are the compounds of formula I, wherein R^(d) isalkyl, cyclohexyl, phenyl, benzyl or allyl.

[0086] Further preferred are the compounds of formula I, wherein R^(e)is hydrogen.

[0087] Examples of preferred compounds of formula I are:

[0088] 1.(R)-6-Chloro-4-methyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;

[0089] 2.(4R,9aR)-6-Chloro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0090] 3.(4R,9aS)-6-Chloro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0091] 4.(R)-6-Bromo-4-methyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;

[0092] 5.(4R,9aR)-6-Bromo-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0093] 6.(4R,9aS)-6-Bromo-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0094] 7. (R)-4,6-Dimethyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;

[0095] 8.(4R,9aR)-4,6-Dimethyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0096] 9.(4R,9aR)-6-Ethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0097] 10.(4R,9aR)-4-Methyl-6-trifluoromethyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0098] 11.(4R,9aR)-6-Cyclopropyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0099] 12.(4R,9aR)-3-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-acrylicacid ethyl ester;

[0100] 13.(4R,9aR)-6-(3-Methoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0101] 14.(4R,9aR)-4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene-6-carbonitrile;

[0102] 15.(4R,9aR)-6-Cyclopropylmethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0103] 16.(4R,9aR)-6-(2-Methoxy-ethoxymethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0104] 17.(4R,9aR)-6-Methoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0105] 18. (R)-4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0106] 19.(4R,9aR)-4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylamine;

[0107] 20.(R)-6-Chloro-4,9-dimethyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;

[0108] 21.(4R,9aR)-6-Benzyloxy-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0109] 22.(4R,9aR)-6-Methoxy-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0110] 23.(4R,9aR)-6-Ethoxy-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0111] 24.(4R,9aR)-2-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yloxy)-ethanol;

[0112] 25.(4R,9aR)-6-(2-Methoxy-ethoxy)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0113] 26.(4R,9aR)-6-Cyclobutylmethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0114] 27.(4R,9aR)-6-Ethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0115] 28.(4R,9aR)-6-Cyclohexylmethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0116] 29.(4R,9aR)-2-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethoxy)-ethanol;

[0117] 30.(4R,9aR)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-methanol;

[0118] 31.(4R,9aR)-6-Isobutyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0119] 32.(4R,9aR)-6-Difluoromethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0120] 33.(4R,9aR)-6-Fluoromethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0121] 34.(4R,9aR)-1-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethanone;

[0122] 35.(4R,9aR)-1-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propan-1-one;

[0123] 36.(4R,9aR)-1-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-butan-1-one;

[0124] 37.(4R,9aR)-2,2,2-Trifluoro-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethanone;

[0125] 38.(4R,9aR)-1-(RS)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethanol;

[0126] 39.(4R,9aR)-6-(1-(R)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene;

[0127] 40.(4R,9aR)-6-(1-(S)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene;

[0128] 41.(4R,9aR)-6-(1-(R)-Methoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0129] 42.(4R,9aR)-6-(1-(S)-Methoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0130] 43.(4R,9aR)-6-(1-(R)-Ethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0131] 44.(4R,9aR)-6-(1-(R)-Cyclopropylmethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0132] 45.(4R,9aR)-6-(1-(S)-Ethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0133] 46.(4R,9aR)-6-(1-(S)-Cyclopropylmethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0134] 47.(4R,9aR)-3,3,3-Trifluoro-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-(R)-propan-1-ol;

[0135] 48.(4R,9aR)-3,3,3-Trifluoro-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-(S)-propan-1-ol;

[0136] 49.(4R,9aR)-(R)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-traza-fluoren-6-yl)-thiazol-2-yl-methanol;

[0137] 50.(4R,9aR)-(S)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-thiazol-2-yl-methanol;

[0138] 51.(4R,9aR)-2-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propan-2-ol;

[0139] 52.(4R,9aR)-3-Methyl-2-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-butan-2-ol;

[0140] 53.(4R,9aR)-1-Methoxy-2-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propan-2-ol;

[0141] 54.(4R,9aR)-5-Chloro-2-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-pentan-2-ol;

[0142] 55.(4R,9aR)4-Methyl-6-(2-(RS)-methyl-tetrahydro-furan-2-yl)-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0143] 56.(4R,9aR)-6-((RS)-1-Fluoro-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0144] 57.(4R,9aR)-6-((RS)-1-Fluoro-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0145] 58.(4R,9aR)-6-((RS)-1-Fluoro-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0146] 59.(4R,9aR)-6-Ethylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene;

[0147] 60.(4R,9aR)-6-Allylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene;

[0148] 61.(4R,9aR)-6-Propylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene;

[0149] 62.(4R,9aR)-6-Isopropylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene;

[0150] 63.(4R,9aR)-6-(1-(RS)-Methoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0151] 64.(4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0152] 65.(4R,9aR)-6-(1-(RS)-Methoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0153] 66.(4R,9aR)-6-(1-(RS)-Ethoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0154] 67.(4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0155] 68. (4R,9aR)-Isopropyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene-6-ylmethylester;

[0156] 69. (4R,9aR)-tert-Butyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;

[0157] 70. Cyclohexyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;

[0158] 71. (4R,9aR)-Ethyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;

[0159] 72. (4R,9aR)-Phenyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;

[0160] 73. (4R,9aR)-Benzyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;

[0161] 74. (4R,9aR)-Allyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;

[0162] 75. (4R,9aR)-Ethyl-carbamic acid1-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propylester;

[0163] 76. (4R,9aR)-Ethyl-carbamic acid1-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-butylester;

[0164] 77. (4R,9aR)-Ethyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester;

[0165] 78. (4R,9aR)-Propyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester;

[0166] 79. (4R,9aR)-Isopropyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester;

[0167] 80. (4R,9aR)-Pyrrolidine-1-carboxylic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;and

[0168] 81. (4R,9aR)-Piperazine-1,4-dicarboxylic acid benzyl ester4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester.

[0169] Examples of particularly preferred compounds of formula I are:

[0170](4R,9aR)-6-Chloro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0171](4R,9aR)-6-Bromo-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0172] (R)-4,6-Dimethyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;

[0173](4R,9aR)-4,6-Dimethyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0174](4R,9aR)-6-Ethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0175](4R,9aR)-4-Methyl-6-trifluoromethyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0176](4R,9aR)-6-Cyclopropyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0177](4R,9aR)-6-Cyclopropylmethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0178](4R,9aR)-6-Methoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0179](R)-6-Chloro-4,9-dimethyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;

[0180](4R,9aR)-6-Difluoromethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0181](4R,9aR)-6-Fluoromethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0182](4R,9aR)-6-(1-(S)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene;

[0183](4R,9aR)-6-(1-(S)-Methoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0184](4R,9aR)-6-(1-(S)-Ethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;

[0185](4R,9aR)-6-(1-(S)-Cyclopropylmethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;and

[0186](4R,9aR)-6-Allylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene.

[0187] Another embodiment of the current invention relates to processesfor the manufacture of the compounds of formula I. The substituents andindices used in the following schemes have the significance given aboveunless otherwise indicated.

[0188] In case R³ is hydroxyalkyl the hydroxy group can be protected inthe following reactions by methods known to one skilled in the art, suchas for example, with tert-butyl-dimethylsilyl.

[0189] 1,2,3,4-Tetrahydro[2,4a,5]triaza-fluorenes of formula II and IIIcan be prepared according to scheme 1 by a process where the7-aza-indole-2-carboxylate of formula A is first reacted with an alphahalo alkanenitrile (e.g., 2-bromo propionitrile) in a suitable solvent(e.g., DMF) with a suitable base (e.g., sodium hydride). Compounds offormula II correspond to compounds of formula I, wherein R² and R⁴ arehydrogen. Compounds of formula III correspond to compounds of formula I,wherein R² is alkyl or alkoxy and R⁴ is hydrogen.

[0190] The intermediate B is reduced and cyclized to thetetrahydro[2,4a,5]triaza-fluorene II or III by reaction with a suitablereducing agent in a suitable solvent (e.g., LiAlH₄ in THF or diethylether). R^(a) in scheme 1 is an alkyl group, preferably a lower alkylgroup, preferably methyl or ethyl.

[0191] Preparation of Compounds According to Formula A:

[0192] Compound of formula A, wherein R¹ is hydrogen or halogen,particularly chlorine are described in WO 0044753.

[0193] Compounds of formula A, wherein R¹ is defined as before with theproviso that R¹ is not hydrogen can be obtained by an analogous processas described in WO 0044753 by, e.g. oxidation of the pyridine nitrogento the N-oxide under appropriate oxidizing conditions, such asmeta-chloroperoxybenzoic acid in dichloromethane and treatment of theN-oxide with a nucleophilic system, such as neat acetic acid anhydrideor benzoic acid bromide in the presence of a suitable base, like e.g.hexamethyldisilazane in a suitable solvent such as, e.g.tetrahydrofuran. The indole nitrogen can be optionally protected in thisprocess, preferably with a Boc group.

[0194] Compound of formula A, wherein R¹ is as defined above with theproviso that R¹ is not halogen, can also be obtained by analogousprocess as described in Synthesis 1996, 877 from N-protected (preferablyBoc) 3-alkyl-2-aminopyridines, through double deprotonation with a base,such as n-butyllithium in a suitable solvent like, e.g. tetrahydrofuranand subsequent treatment of the intermediate with diethyloxalate anddehydration of the resulting adduct under acidic conditions, e.g. withhydrochloric acid in an appropriate alcohol, such as, e.g. ethanol.

[0195] Compounds according to formula A, particularly in case R² isalkoxy, can also be synthesized in a process where2-(ethoxycarbonylmethyl-amino)-nicotinic acid ethyl esters, which can beobtained by, e.g. reaction of 2-amino-nicotinic acid ethyl ester withglyoxal and perchloric acid in ethanol, are cyclized to thecorresponding 3-hydroxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acidethyl esters which in turn are alkylated with suitable alkylating agentsin an appropriate solvent (e.g. ethyl iodide in tetrahydrofuran).

[0196] Alpha halo alkanenitriles can be either purchased from commercialsources or synthesized from, e.g. reaction of acrylonitrile withbromoalkanes under UV irradiation in the presence of, e.g.triphenylphosphine and a suitable catalyst such as copper(I)chloride inan appropriate solvent like, e.g. tetrahydrofuran (analogous to theprocess described in J. Am. Chem. Soc. 1983, 105(22), 6719). Alpha haloalkanenitriles can also be prepared in a process, where analkoxyacetonitrile derivative is irradiated in the presence of asuitable brominating agent like, e.g. N-bromosuccinimide intetrahydrofuran (analogous to the process described in J. Org. Chem.1976, 14 (17), 2846). In the case of R³ is hydroxymethyl the free OHgroup is protected.

[0197] 1,2,3,4-Tetrahydro[2,4a,5]triaza-fluorenes of formula II and IIIcan also be prepared according to scheme 2 by a process where the7-aza-indole-2-carboxylate of formula A is first reacted with theBoc-sulfamidate X in a suitable solvent (e.g., DMF) with a suitable base(e.g., potassium tert-butylate or sodium hydride) followed by removal ofthe Boc protecting group (Boc means tert-butoxycarbonyl) with a suitablereagent e.g. trifluoroacetic acid (TFA) and ring closure in the presenceof base (e.g., potassium carbonate). The stereochemistry of the carbonatom attached to R³ in Boc-sulfamidate X is inverted (>90% e.e.) in thisreaction sequence. The intermediate amide D is reduced with a suitablereducing agent in a suitable solvent (e.g., LiAlH₄ in tert-butyl methylether or borane-dimethylsulfide complex in THF). R^(a) in scheme 2 is analkyl group, preferably a lower alkyl group, preferably methyl or ethyl.In case R³ means hydroxyalkyl the corresponding hydroxy group can beprotected by, e.g. a tert-butyl-dimethylsilyl group. Compounds II andIII are defined as in scheme 1.

[0198] Chiral compounds according to formulae II and III can e.g. beobtained as follows:

[0199] If racemic Boc-sulfamidate X is used in this process, theenantiomers of intermediate D can be obtained by methods known in theart, e.g., by preparative chiral HPLC.

[0200] The enantiomers of 1,2,3,4-tetrahydro[2,4a,5]triaza-fluorenes IIand III can be obtained either by using a chiral sulfamidate X or byseparation of the enantiomers by preparative chiral HPLC or bycrystallization with suitable chiral acids, separation of thediastereomeric salts and isolation of the enantiomers from these salts.An alternative access to the enantiomers of1,2,3,4-tetrahydro[2,4a,5]triaza-fluorenes II and III involves theseparation of the enantiomers of the precursor C, e.g., by preparativechiral HPLC.

[0201] 7-Aza-indole derivatives H can be prepared according to scheme 5,starting from protected o-iodoanilines (PG¹ means a suitable protectivegroup such as e.g. N-methoxycarbonyl) by cross-coupling reaction withsuitably substituted and optionally protected carbinols (preferredprotective groups PG² are silyl ethers, especially preferred istert-butyl-dimethylsilyl). The reaction proceeds in the presence of asuitable catalyst (e.g., bis-triphenylphosphine palladium dichloride andcopper(I)iodide as co-catalyst) in a suitable solvent (e.g.triethylamine). The intermediate E is treated with a base (e.g. LiOH inTHF/water) to yield the indole derivative F. After deprotection (e.g.,with tetrabutylammonium fluoride) in a suitable solvent (e.g., THF), theresulting alcohol is oxidized (e.g., with manganese dioxide indichloromethane), to yield the indole derivative G. Alkylation of G withthe Boc-sulfamidate X in a suitable solvent (e.g., DMF) in the presenceof a suitable base (e.g., sodium hydride or potassium tert-butylate)leads to intermediate H. The stereochemistry of the carbon atom attachedto R³ in Boc-sulfamidate X is inverted (>90% e.e.) in this reactionsequence.

[0202] Alternatively, compounds of formula H can be prepared accordingto scheme 6 below:

[0203] 7-Aza-indole derivatives H can also be prepared according toscheme 6, starting from protected o-iodoanilines (a suitable protectivegroup, PG 1, is, e.g. N-methoxycarbonyl) by cross-coupling reaction withpropargyl alcohol derivatives in the presence of a suitable catalyst(e.g., bis-triphenylphosphine palladium dichloride and copper(I)iodideas co-catalyst) in a suitable solvent (e.g. triethylamine), followed bytreatment with a base (e.g. LiOH in THF/water). The alcohol intermediateis oxidized, e. g. with manganese dioxide in dichloromethane, to yieldthe indole derivative G. Alkylation of G with the Boc-sulfamidate X in asuitable solvent (e.g., DMF) in the presence of a suitable base (e.g.,potassium tert-butylate or sodium hydride) leads to intermediate H. Thestereochemistry of the carbon atom attached to R³ in Boc-sulfamidate Xis inverted (>90% e.e.) in this reaction sequence.

[0204] As described in scheme 7, the intermediates of formula H can befurther processed to compounds of formula II by either removal of theBoc protecting group (e.g., with trifluoroacetic acid) to yield an imineintermediate which is not isolated but reduced directly with lithiumaluminum hydride to yield II as a separable mixture of epimers, ordirect reductive amination (e.g., with sodium triacetoxyborohydride,molecular sieves and acetic acid in a suitable solvent, e.g.,dichloromethane) to yield compound IV, followed by removal of theprotecting group (e.g., with hydrochloric acid in ethyl acetate).

[0205] A variety of substituents R², preferably those functional groupsthat do not tolerate the methods described for the1,2,3,4-tetrahydro[2,4a,5]triaza-fluorenes synthesis can be introducedstarting from 1,2,3,4-tetrahydro[2,4a,5]triaza-fluorene IV according toscheme 8. To that end, the amine nitrogen of II may be protected, e.g.,as the tert-butyl carbamate, to generate compounds of formula IV.

[0206] 1,2,3,4-Tetrahydro[2,4a,5]triaza-fluorenes of formula III inwhich R² equals a methyl substituent can also be prepared as depicted inscheme 9 from intermediate IV by a two step process where an aldehydemoiety is first introduced by, e.g. a Vilsmeier-Haack formylationreaction and subsequent reduction of the formyl intermediate undersuitable conditions (e.g., triethylsilane and trifluoroacetic acid indichloromethane). Under these conditions the protective group may alsobe cleaved-off, e.g. if it is a tert-butyl carbamate group.

[0207] The hexahydro[2,4a,5]triaza-fluorene derivatives of formula V canbe prepared as described in scheme 10 from compounds of formula II orIII (analogous to WO 0044753) or IV by reduction with suitable reducingagents in suitable solvents or solvent mixtures (e.g. THF/TFA or NaCNBH₃in acetic acid, respectively). Compounds of formula V may also beprepared from compounds of formula II or III (analogous to WO 0044753)by simultaneous reduction and deprotection of the tert-butoxy carbonylgroup with suitable reducing agents in suitable acidic solvents orsolvent mixtures (e.g. THF/TFA).

[0208] Compounds of formula Ia can also be prepared as shown in scheme11 below:

[0209] Hexahydro[2,4a,5]triaza-fluorene derivatives of formula Ia canalso be prepared as depicted in scheme 11 from intermediate J where theindole moiety is reduced with magnesium in methanol to produceindoline-amide K, which is then reduced under suitable conditions (e.g.,LiAIH₄ in diethyl ether).

[0210] Compounds V can alternatively be prepared as depicted above inscheme 12. Indole intermediates L are reduced with a suitable reducingagent (e.g., magnesium in methanol). The indoline derivative M isalkylated with an alkylating agent such as, e.g. the sulfamidate.X inthe presence of a suitable base like, e.g. sodium hydride in a suitablesolvent such as N,N-dimethylformamide. Intermediate K can be prepared bysequential treatment of intermediate N with an acid (e.g.trifluoroacetic acid in dichloromethane) followed by a base like, e.g.potassium carbonate in methanol. Reduction of intermediate K with asuitable reducing agent such as lithium aluminum hydride in a suitablesolvent such as, e.g. tetrahydrofuran or diethyl ether yieldsderivatives V. In case R³ means hydroxyalkyl the corresponding hydroxygroup can be protected by e.g. a tert-butyl-dimethylsilyl group.

[0211] PG means a protective group compatible with the chemicaltransformation, e.g. as described in T. W. Greene and P. G. M. Wuts,Protective groups in organic synthesis, 2^(nd) edition, pp. 309;preferably Boc.

[0212] R^(a) is defined as before and R⁷ is alkyl, aryl, cycloalkyl,alkoxyalkyl or aryloxyalkyl.

[0213] R⁵ and R⁶ are hydrogen or alkyl or R⁵ and R⁶ together with the Natom to which they are attached form a ring, such as morpholin-1-yl,pyrrolidinyl or piperidinyl.

[0214] Compounds according to formula IX can be obtained according toscheme 2 and following reduction according to scheme 10.

[0215] A variety of substituents R¹, preferably those functional groupsthat do not tolerate the methods described for thehexahydro[2,4a,5]triaza-fluorene synthesis can be introduced startingfrom the hexahydro[2,4a,5]triaza-fluorene derivative IX.

[0216] Several examples for the elaboration of compound IX arehighlighted in scheme 13 above.

[0217] a) Amine derivatives O (by, e.g. cross-coupling reaction withbenzophenone imine in the presence of a base like, e.g. sodiumtert-butoxide and an appropriate catalyst like, e.g.tris(dibenzylideneacetone)dipalladium chloroform complex andR-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene as ligand in asuitable solvent like, e.g. toluene and cleavage of the iminefunctionality (with, e.g. palladium on charcoal and ammonium formate inmethanol). The amine substituent can be further alkylated or convertedinto amides or sulfonamides by methods known in the art. In the casewhere the substituents R⁵ and R⁶ together form a ring like in, e.g.morpholine, the substituent can be introduced with, e.g. palladium(II)acetate, 2,2′-dihydroxy-1,1′-dinaphthyl, sodium tert-butylate andmorpholine in toluene.

[0218] b) Ester-substituted derivatives P (e.g. via bromine-lithiumexchange, quenching the lithium intermediate with carbon dioxide andesterification of the acid) or via carbonylation reactions (e.g. under acarbon monoxide atmosphere with a suitable catalyst like, e.g.bis(triphenylphosphine)palladium(II) chloride in an appropriate alcohollike, e.g. methanol or ethanol in the presence of a base like, e.g.triethylamine), which can be further converted into amides (T) orreduced to benzylic alcohols (U), the latter again can be alkylated orarylated by methods known to those skilled in the art.

[0219] c) Cyano derivative Q (e.g. with copper(I)cyanide andtetraethylammonium cyanide, tris(dibenzylideneacetone)dipalladium(O) ascatalyst and 1,1′-bis(diphenylphosphino) ferrocene as ligand indioxane), which can be further reduced to the benzylic amine, which inturn can be alkylated and acylated, respectively by methods known tothose skilled in the art.

[0220] d) α,β-Unsaturated ester derivatives R (e.g. throughcross-coupling reaction with ethyl acrylate with allylpalladium chloridedimer as catalyst, an appropriate base like, e.g. sodium acetate andtri(o-tolyl)phosphine as ligand in toluene), which can be furtherderivatized to yield α,β-unsaturated amides, or reduced to the allylicalcohol (W, R⁷ is H) derivative which again can be optionally alkylatedby methods known to those skilled in the art.

[0221] e) Alkyl, trifluoromethyl, or cyclopropyl derivatives S (Forexample, a methyl group can be introduced through cross-couplingreaction with trimethylboroxine in the presence of a catalyst like, e.g.tetrakis(triphenylphosphine)palladium(O) and an appropriate base like,e.g. sodium carbonate in a solvent mixture like, e.g. dimethoxyethaneand water. A trifluoromethyl substituent can be introduced throughreaction of intermediate IX with, e.g. trifluoroacetate andcopper(I)iodide in an appropriate solvent like, e.g.1-methyl-2-pyrrolidone. A cyclopropyl substituent can be introduced forexample through palladium-catalyzed (e.g. tetrakis(triphenylphosphine)palladium(0)) reaction of IX with a pre-formed complex of9-borabicyclo[3.3.1]nonane and propargylbromide in the presence of anappropriate base like, e.g. sodium hydroxide in an appropriate solventlike, e.g. tetrahydrofuran.

[0222] Cleavage of the protective group in compounds according toformula Ic, wherein PG means a protecting group, preferably Boc, can beperformed, e.g. with acid such as trifluoroacetic acid or hydrogenchloride in a suitable solvent such as ethyl acetate in order to obtaina compound of formula Id.

[0223] The tetra-and hexahydro[2,4a,5]triaza-fluorenes of formula Ib andIa can be prepared from compounds of formula II, III and V,respectively, by methods known in the art (e.g. March, Advanced OrganicChemistry, 4 th. edition, page 411ff, 768ff, 898ff, 900ff, 1212ff.),e.g. alkylation reactions (e.g. with R⁴—Br under basic conditions),Mannich reactions or acylation followed by reduction etc.

[0224] The Boc-sulfamidate X can be prepared according to scheme 16 bytreating Boc-protected ethanolamine derivatives with thionyl chloride ina suitable solvent e.g. THF or ethyl acetate in the presence of asuitable base e.g. triethylamine or imidazole and oxidizing theintermediate (e.g., with sodium metaperiodate and ruthenium(IV)oxide) ina suitable solvent (e.g., ethyl acetate). Where R³ is not hydrogen, thestereochemistry of the carbon atom attached to R³ remains unchanged(e.e. >97%) over this sequence.

[0225] As mentioned above, one embodiment of the current inventionrelates to the use of compounds of formula I, or their pharmaceuticallyacceptable salts, solvates or esters, to treat illnesses that are causedby disorders associated with the 5-HT₂ receptors, specifically the5-HT_(2A), 5-HT_(2B) and 5-HT_(2C) receptor subtypes, more particularlythe 5-HT_(2C) receptor subtype.

[0226] The invention also relates to pharmaceutical compositionscomprising a therapeutically effective amount of a compound of formulaI, or a pharmaceutically acceptable salt, solvate or ester thereof, anda therapeutically inert carrier.

[0227] The present invention also relates to a method for the treatmentand prophylaxis of eating disorders and obesity comprising administeringto a patient in need of such therapy a therapeutically effective amountof a compound of formula I.

[0228] In another embodiment, the invention relates to the use of acompound of formula I, or a pharmaceutically acceptable salt, solvate orester thereof, for the treatment and prophylaxis of diabetes mellitus(DM) including Type I diabetes (insulin dependent diabetes mellitus(IDDM)), Type II diabetes (non-insulin dependent diabetes mellitus(NIDDM)), diabetes secondary to pancreatic disease, diabetes related tosteroid use, Type III diabetes (malnutrition related diabetes), diabetesinsipidus, hyperglycaemia, diabetic complications and insulinresistance.

[0229] It is a further particularly preferred object of the invention toprovide a pharmaceutical composition comprising a compound of formula I,or a pharmaceutically acceptable salt, solvate or ester thereof, for thetreatment of Type II diabetes (non-insulin dependent diabetes mellitus(NIDDM)).

[0230] Another embodiment of the invention relates to a pharmaceuticalcomposition for the treatment of disorders of the central nervoussystem, cardiovascular disorders, gastrointestinal disorders, diabetesinsipidus and sleep apnoea, comprising a therapeutically effectiveamount of a compound of formula I, or a pharmaceutically acceptablesalt, solvate or ester thereof, and an inert carrier.

[0231] Particularly an object of the invention is a composition to treatdisorders of the central nervous system are selected from depression,atypical depression, bipolar disorders, anxiety disorders,obsessive-compulsive disorders, social phobias or panic states, sleepdisorders, sexual dysfunction, psychoses, schizophrenia, migraine andother conditions associated with cephalic pain or other pain, raisedintracranial pressure, epilepsy, personality disorders, age-relatedbehavioural disorders, behavioural disorders associated with dementia,organic mental disorders, mental disorders in childhood, aggressivity,age-related memory disorders, chronic fatigue syndrome, drug and alcoholaddiction, bulimia, anorexia nervosa, premenstrual tension, trauma,stroke, neurodegenerative diseases, encephalitis and meningitis.

[0232] A further preferred embodiment of the present invention is acomposition as above-described to treat thrombosis.

[0233] Also preferred is the aforementioned use of the compoundsaccording to formula I, wherein the gastrointestinal disorder isdysfunction of gastrointestinal motility.

[0234] A further object of the invention are compounds in accordancewith formula I, when manufactured according to the processess describedherein.

[0235] A further embodiment of the present invention is a method for thetreatment and prophylaxis of disorders of the central nervous system,cardiovascular disorders, gastrointestinal disorders, diabetes insipidusand sleep apnoea, which method comprises administering an effectiveamount of a compound of formula I as described.

[0236] Preferred is this method, wherein the disorders of the centralnervous system are selected from depression, atypical depression,bipolar disorders, anxiety disorders, obsessive-compulsive disorders,social phobias or panic states, sleep disorders, sexual dysfunction,psychoses, schizophrenia, migraine and other conditions associated withcephalic pain or other pain, raised intracranial pressure, epilepsy,personality disorders, age-related behavioural disorders, behaviouraldisorders associated with dementia, organic mental disorders, mentaldisorders in childhood, aggressivity, age-related memory disorders,chronic fatigue syndrome, drug and alcohol addiction, bulimia, anorexianervosa, premenstrual tension, trauma, stroke, neurodegenerativediseases, encephalitis and meningitis.

[0237] Preferred is a method for the treatment and prophylaxis ofdiabetes mellitus (DM), Type I diabetes (insulin dependent diabetesmellitus (IDDM)), Type II diabetes (non-insulin dependent diabetesmellitus (NIDDM)), diabetes secondary to pancreatic disease, diabetesrelated to steroid use, type III diabetes (malnutrition relateddiabetes), diabetes insipidus, hyperglycemia, diabetic complications andinsulin resistance, which method comprises administering an effectiveamount of a compound in accordance with formula I.

[0238] Particularly preferred is a method for the treatment andprophylaxis of diabetes mellitus (DM), Type I diabetes (insulindependent diabetes mellitus (IDDM)), Type II diabetes (non-insulindependent diabetes mellitus (NIDDM)), diabetes secondary to pancreaticdisease, diabetes related to steroid use, type III diabetes(malnutrition related diabetes), hyperglycemia, diabetic complicationsand insulin resistance, which method comprises administering aneffective amount of a compound in accordance with formula I.

[0239] It is a preferred object of the invention to provide a method forthe treatment and prophylaxis of eating disorders and obesity, whichmethod comprises administering an effective amount of a compound offormula I.

[0240] It is a preferred object of the invention to provide a method forthe treatment and prophylaxis of Type II diabetes (non-insulin dependentdiabetes mellitus (NIDDM), which method comprises administering aneffective amount of a compound of formula I.

[0241] It is a further preferred object of the invention to provide amethod of treatment of obesity in a human which comprises administrationof a therapeutically effective amount of a compound according to formulaI and a therapeutically effective amount of a lipase inhibitor,particularly, wherein the lipase inhibitor is orlistat. Also an objectof the invention is the method as described above for the simultaneous,separate or sequential administration.

[0242] It is a further preferred object to provide a method of treatmentof Type II diabetes (non-insulin dependent diabetes mellitus (NIDDM) ina human which comprises administration of a therapeutically effectiveamount of a compound according to formula I and a therapeuticallyeffective amount of a lipase inhibitor, particularly, wherein the lipaseinhibitor is orlistat. Also an object of the invention is the method asdescribed above for the simultaneous, separate or sequentialadministration of a compound according to formula I and a lipaseinhibitor, particularly orlistat.

[0243] It is a further preferred object of the invention to provide amethod of treatment of diabetes mellitus (L)M), Type I diabetes (insulindependent diabetes mellitus (IDDM)), Type II diabetes (non-insulindependent diabetes mellitus (NIDDM)), diabetes secondary to pancreaticdisease, diabetes related to steroid use, Type III diabetes(malnutrition related diabetes), diabetes insipidus, hyperglycaemia,diabetic complications and insulin resistance in a human which comprisesadministration a therapeutically effective amount of a compoundaccording to formula I and a therapeutically effective amount of alipase inhibitor, particularly, wherein the lipase inhibitor isorlistat. It is also an object of the invention to provide a method asdescribed above for the simultaneous, separate or sequentialadministration of a compound according to formula I and a lipaseinhibitor, particularly orlistat.

[0244] It is a further particularly preferred object of the invention toprovide a method of treatment of diabetes mellitus (DM), Type I diabetes(insulin dependent diabetes mellitus (IDDM)), Type II diabetes(non-insulin dependent diabetes mellitus (NIDDM)), diabetes secondary topancreatic disease, diabetes related to steroid use, Type III diabetes(malnutrition related diabetes), hyperglycaemia, diabetic complicationsand insulin resistance in a human which comprises administration atherapeutically effective amount of a compound according to formula Iand a therapeutically effective amount of a lipase inhibitor,particularly, wherein the lipase inhibitor is orlistat. It is also anobject of the invention to provide a method as described above for thesimultaneous, separate or sequential administration of a compoundaccording to formula I and a lipase inhibitor, particularly orlistat.

[0245] A further object of the invention is the use of a compound offormula I in the manufacture of a medicament for the treatment andprevention of obesity in a patient who is also receiving treatment witha lipase inhibitor and particularly, wherein the lipase inhibitor isorlistat.

[0246] A further object of the invention is the use of a compound offormula I in the manufacture of a medicament for the treatment andprevention of Type II diabetes (non-insulin dependent diabetes mellitus(NIDDM)) in a patient who is also receiving treatment with a lipaseinhibitor and particularly, wherein the lipase inhibitor is orlistat.

[0247] A further preferred object of the present invention is the use ofa compound according to formula I in the manufacture of a medicament forthe treatment and prevention of diabetes mellitus (DM), Type I diabetes(insulin dependent diabetes mellitus (IDDM)), Type II diabetes(non-insulin dependent diabetes mellitus (NIDDM)), diabetes secondary topancreatic disease, diabetes related to steroid use, Type III diabetes(malnutrition related diabetes), diabetes insipidus, hyperglycaemia,diabetic complications and insulin resistance in a patient who is alsoreceiving treatment with a lipase inhibitor particularly, wherein thelipase inhibitor is orlistat.

[0248] A further particularly preferred object of the present inventionis the use of a compound according to formula I in the manufacture of amedicament for the treatment and prevention of diabetes mellitus (DM),Type I diabetes (insulin dependent diabetes mellitus (IDDM)), Type IIdiabetes (non-insulin dependent diabetes mellitus (NIDDM)), diabetessecondary to pancreatic disease, diabetes related to steroid use, TypeIII diabetes (malnutrition related diabetes), hyperglycaemia, diabeticcomplications and insulin resistance in a patient who is also receivingtreatment with a lipase inhibitor particularly, wherein the lipaseinhibitor is orlistat.

[0249] It is also an object of the invention to provide a pharmaceuticalcomposition comprising a compound of formula I, a therapeutically inertcarrier and a therapeutically effective amount of a lipase inhibitor,particularly, wherein the lipase inhibitor is orlistat.

[0250] Other combinations which may be considered are Sibutraminecomprising combinations.

[0251] It is also a preferred object of the invention to provide amethod of treatment and/or prevention in mammals disorders where areduction of the blood glucose concentration is beneficial comprisingadministering a therapeutically effective amount of a compound offormula I. Particularly preferred is this use or method wherein thedisorders are disorders involving elevated plasma blood glucose.

[0252] The compounds of formula (I) may be used in the treatment(including prophylactic treatment) of disorders associated with 5-HT₂receptor function. The compounds may act as receptor agonists orantagonists. Preferably, the compounds may be used in the treatment(including prophylactic treatment) of disorders associated with5-HT_(2B) and/or 5-HT_(2C) receptor function. Preferably, the compoundsmay be used in the treatment (including prophylactic treatment) ofdisorders where a 5-HT_(2C) receptor agonist is required.

[0253] A further preferred embodiment of the present invention is aprocess for the preparation of a compound of formula I, comprising anyone of the following reactions:

[0254] a) reduction of a compound of formula B to obtain a compound offormula Ib

[0255] wherein R¹ to R³ are defined as in claim 1, R⁴ means hydrogen andR^(a) means alkyl, preferably methyl or ethyl; a preferred reducingagent is e.g. LiALH₄, particularly in THF or diethyl ether; or

[0256] b) reduction of a compound of formula D, preferably with e.g.LiAlH₄, particularly in tert-butyl methyl ether orborane-dimethylsulfide complex in THF to obtain a compound of formula Ib

[0257] wherein R¹ to R³ are defined as in claim 1 and, wherein R⁴ ishydrogen; or

[0258] c) reduction of a compound according to formula Ib preferablywith a reducing agent in a suitable solvent or solvent mixtures e.g.THF/TFA or NaCNBH₃ in acetic acid to obtain a compound of formula Ia

[0259] wherein R¹ to R⁴ are defined as in claim 1 and, wherein R⁴ meanspreferably hydrogen; or

[0260] d) reduction of a compound according to formula K, preferablywith e.g. LiAlH₄, particularly in diethyl ether or THF

[0261] wherein R¹ to R⁴ are defined above; or

[0262] e) cleavage of the protective group (PG) of a compound accordingto formula Ic, preferably in the presence of acid such astrifluoroactetic acid or HCl in a suitable solvent such as ethyl acetatein order to obtain a compound of formula Id

[0263] wherein R¹ to R³ are defined as in claim 1. A preferredprotecting group (PG) is the Boc group.

[0264] In another embodiment, the current invention includes thefollowing novel intermediates:

[0265](4R,10aR)-6-Bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester;

[0266] 7-Oxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester;

[0267] 6-Bromo-pyrrolo [2,3-b]pyridine-1,2-dicarboxylic acid1-tert-butyl ester 2-ethyl ester;

[0268] 6-Bromo-1H-pyrrolo [2,3-b]pyridine-2-carboxylic acid ethyl ester;

[0269] 6-Hydroxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethylester; and

[0270] 6-Hydroxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid1-tert-butyl ester 2-ethyl ester.

[0271] The processes as described above may be carried out to give acompound of the invention in the form of a free base or as an acidaddition salt. If the compound of the invention is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid addition salt. Conversely, if the product of the process is afree base, an acid addition salt, particularly a pharmaceuticallyacceptable acid addition salt, may be obtained by dissolving the freebase in a suitable organic solvent and treating the solution with anacid, in accordance with conventional procedures for preparing acidaddition salts from basic compounds.

[0272] The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) transdermal or rectal administration orin a form suitable for administration by inhalation or insufflation.

[0273] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g. pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g. magnesium stearate,talc or silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulfate). The tabletsmay be coated by methods well known in the art. Liquid preparations fororal administration may take the form of, for example, solutions, syrupsor suspensions, or they may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters or ethyl alcohol); and preservatives (e.g.methyl or propyl p-hydroxybenzoates or sorbic acid).

[0274] For buccal administration the composition may take the form oftablets or lozenges formulated in conventional manner.

[0275] The active compounds of the invention may be formulated forparenteral administration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form e.g. in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents.

[0276] Alternatively, the active ingredient may be in powder form forreconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

[0277] The active compounds of the invention may also be formulated inrectal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

[0278] For intranasal administration or administration by inhalation,the active compounds of the invention are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoro-ethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

[0279] A proposed dose of the active compounds of the invention fororal, parenteral or buccal administration to the average adult human forthe treatment of the conditions referred to above (e.g., obesity) is 0.1to 500 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

[0280] The invention will now be described in detail with reference tothe following examples. It will be appreciated that the invention isdescribed by way of example only and modification of detail may be madewithout departing from the scope of the invention.

Assay Procedures

[0281] 1. Binding to Serotonin Receptors

[0282] The binding of compounds of formula (I) to serotonin receptorswas determined in vitro by standard methods. The activity of the testcompounds was investigated in accordance with the assays given below.

[0283] Method (a):

[0284] For the binding to the 5-HT_(2C) receptor, the 5-HT_(2C)receptors were radiolabeled with [³H]-5-HT. The affinity of thecompounds for 5-HT_(2C) receptors in a CHO cell line was determinedaccording to the procedure of D. Hoyer, G. Engel and H.O. Kalkman,European J. Pharmacol., 1985, 118, 13-23.

[0285] Method (b):

[0286] For the binding to the 5-HT_(2B) receptor, the 5-HT_(2B)receptors were radiolabeled with [³H]-5-HT. The affinity of thecompounds for human 5-HT_(2B) receptors in a CHO cell line wasdetermined according to the procedure of K. Schmuck, C. Ullmer, P.Engels and H. Lubbert, FEBS Lett., 1994, 342, 85-90.

[0287] Method (c):

[0288] For the binding to the 5-HT_(2A) receptor, the 5-HT_(2A)receptors were radiolabeled with [¹²⁵I]-DOI. The affinity of thecompounds for 5-HT_(2A) receptors in a CHO cell line was determinedaccording to the procedure of D. J. McKenna and S. J. Peroutka, J.Neurosci., 1989, 9, 3482-90.

[0289] The thus determined activity of the compound of the designatedExample is shown in Table 1. TABLE 1 Method (a) Method (b) Method (c)Compound K_(i) (2C) K_(i) (2B) K_(i) (2A) Example 7  8.1 nM 136.9 nM229.0 nM Example 9 16.5 nM 270.8 nM 212.1 nM Example 20  5.1 nM 108.0 nM177.8 nM

[0290] Preferred compounds of formula I as described above have Ki (2C)values below 10000 nM; especially preferred compounds have Ki (2C)values below 1000 nM, particularly preferred compounds have Ki (2C)values below 100 nM. Most preferred compounds have Ki (2C) values below30 nM.

[0291] 2. Functional Activity

[0292] The functional activity of compounds of formula (I) was assayedusing a Fluorimetric Imaging Plate reader (FLIPR). CHO cells expressingthe human 5-HT_(2C) or human 5-HT_(2A) receptors were counted and platedinto standard 96 well microtitre plates on the day before testing togive a confluent monolayer. The cells were then dye loaded with thecalcium sensitive dye, Fluo-3-AM. Unincorporated dye was removed usingan automated cell washer to leave a total volume of 100 μL/well of assaybuffer (Hanks balanced salt solution containing 20 mM Hepes and 2.5 mMprobenecid). The drug (dissolved in 50 μL of the assay buffer) was addedat a rate of 70 μL/sec to each well of the FLIPR 96 well plate duringfluorescence measurements. The measurements were taken at 1 secintervals and the maximum fluorescent signal was measured (approx 10-15secs after drug addition) and compared with the response produced by 10μM 5-HT (defined as 100%) to which it was expressed as a percentageresponse (relative efficacy). Dose response curves were constructedusing Graphpad Prism (Graph Software Inc.). TABLE 2 h5-HT2C h5-HT2A EC₅₀Rel. Eff. EC₅₀ Rel. Eff. Compound [nM] [%] [nM] [%] Example 7 19.2 99.4342.8 21.6 Example 9 85.4 91.4 643.6 29.6 Example 20 7.6 93.3 11.1 12.0

[0293] The compounds of formula (I) have activity at the h5-HT2creceptor in the range of 10,000 to 0.01 nM.

[0294] Preferred compounds of formula I as described above have activityat the h5-HT2c receptor below 10000 nM; especially preferred compoundsbelow 1000 nM, particularly preferred compounds below 100 nM. Mostpreferred compounds have activity at the h5-HT2c receptor below 30 nM.

[0295] 3. Regulation of Feeding Behavior

[0296] The in vivo activity of compounds of formula (1) was assessed fortheir ability to regulate feeding behavior by recording food consumptionin food deprived animals. Rats were trained to have access to food for 2h per day and were food deprived for 22h. When they were trained underthis schedule, the amount of food taken every day during these 2h foodintake session was consistent day after day.

[0297] To test the ability of the 5-HT_(2C) receptor agonists todecrease food intake, 8 animals were used in a cross-over study. Ratswere individually housed in plexiglass boxes with a grid on the floorand a paper was placed below the cage floor to collect any spillage. Afood dispenser (becher) filled with a preweighed amount of food waspresented to them for 2 h. At the end of the food intake session, ratsreturned to their home cage. Each rat was weighed before the start ofthe experiment and the amount of food consumed during this 2 h foodintake session was recorded. Either various doses of test compound orVehicle was administered orally 60 min before the 2 h food intakesession. A positive control Sibutramine was included in the experiment.

[0298] An Anova analysis with repeated measures was used followed by aposthoc test Student Neumann-Keuls. * P<0.05 compared to Saline-treatedrats.

[0299] The minimum effective dose (m.e.d.) is defined as the lowest dosewhich produces a statistically significant reduction in food intake. Theminimum effective doses for selected particularly preferred compounds offormula I are 30 mg/kg p.o. and below.

EXAMPLES Example 1

[0300] (R)-6-Chloro-4-methyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;hydrochloride

[0301] To a solution of 0.3 g (1.3 mmol)(R)-6-chloro-4-methyl-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one in 20ml tert-butyl methyl ether, 0.20 g (5.1 mmol) lithium aluminum hydridewas added and the suspension was heated to reflux for 1 h and cooled toroom temperature. The reaction mixture was poured into 20 ml saturatedaqueous potassium sodium tartrate solution and filtered over dicalitespeed plus. The filtrate was extracted four times with ethyl acetate.The combined organic phases were washed with brine, dried over magnesiumsulfate and filtered. The crude product was purified by chromatographyover silica gel (0.032-0.063 mm) with dichloromethane: methanol (49:1)as eluant. The colorless oil (81%) was dissolved in ethyl acetate and0.6 ml of a 2M hydrochloric acid solution in ethyl acetate was added.The resulting suspension was stirred at 0 deg C. for 15 min andfiltered; the filter-cake was washed with ethyl acetate and dried underhigh vacuum.

[0302] ISP-MS: m/e=222.2 ([M+H⁺])

[0303] Elemental analysis: C₁₁H₁₃Cl₂N₃ (258.152) calc.#): C 51.37 H 5.31N 15.35 Cl 25.90 found: C 51.10 H 5.13 N 15.40 Cl 25.81 #) Calculatedwith 1 mole C₁₁H₁₃Cl₂N₃ and 0.18 mole C₄H₈O₂.

Intermediates

[0304] a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic Acid Ethyl Ester

[0305] A solution of 3.0 g (13.3 mmol)6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in 70ml N,N-dimethylformamide was cooled to 0 deg C. and 1.58 g (14.0 mmol)potassium tert-butoxide was added. After 30 min, 3.49 g (14.7 mmol)(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester was added in one portion. The cooling bath was removedand after 1.5 h the reaction mixture was poured into 100 ml 10% aqueouscitric acid. The layers were separated and the aqueous phase wasextracted three times with ethyl acetate. The combined organic phaseswere washed four times with water, once with brine and then were driedover magnesium sulfate. After filtration the solvent was removed on arotary evaporator and the residue was purified by flash-chromatographyover silica gel (0.032-0.063 mm) with n-hexane:ethyl acetate (9:1, then5:1) as eluant to afford the product as a yellow oil (98.0%). ISP-MS:m/e=382.3 ([M+H⁺])³⁰)

[0306] b)(R)-6-Chloro-4-methyl-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one

[0307] A solution of 6.70 g (17.5 mmol)(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid ethyl ester in 80 ml dichloromethane was cooled to 0 deg C. and 27ml (0.35 mol) trifluoroacetic acid were added over 4 min. The coolingbath was removed and after 1 h the volatile components were removed on arotary evaporator. The residue was dissolved in 40 ml methanol and 9.70g (70.2 mmol) potassium carbonate was added. After stirring for 2.5 hthe reaction mixture was diluted with water and ethyl acetate and thephases were separated. The aqueous phase was extracted three times withethyl acetate. The combined organic layers were washed with brine, driedover magnesium sulfate and filtered. After evaporation, the residue wastaken up in 50 ml tert-butyl methyl ether upon which the product startedto precipitate. The solid was collected by filtration, washed with 20 mlof tert-butyl methyl ether and dried under high vacuum to afford theproduct as a pale yellow powder. The concentrated mother liquors werepurified by flash chromatography over silica gel (0.032-0.063 mm) withethyl acetate as eluant to yield another batch of product (86.6% total).

[0308] EI-MS: m/e=235.2 ([M+H⁺])

Example 2

[0309](4R,9aR)-6-Chloro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;Hydrochloride

[0310] A solution of 0.50 g (1.54 mmol)(4R,9aR)-6-chloro-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 5 ml dichloromethane was cooled to 0 deg C. andtreated with 2.5 ml (3.72 g, 32.7 mmol) trifluoroacetic acid. Thecooling bath was removed and after 1 h at room temperature the volatilecomponents were removed on a rotary evaporator and the residue waspurified by chromatography over silica gel (0.032-0.063 mm) withdichloromethane: methanol: ammonia (9:1:0.1) as eluant. The so-obtainedfree base was dissolved in 8 ml ethyl acetate and treated with 0.85 mlof a 2M hydrochloric acid solution in ethyl acetate. After 1 h theresulting suspension was filtered; the filter-cake was dried under highvacuum to afford the product as colorless crystals (55.5%).

[0311] EI-MS: m/e=224.2 ([M+H⁺])

[0312] Elemental analysis: C₁₁H₁₄ClN₃.HCl (266.731) calc.#): C 49.67 H5.83 N 15.31 Cl 28.16 found: C 49.87 H 5.82 N 15.27 Cl 28.36

[0313] #) Calculated with 1 mole C₁₁H₁₄ClN₃ (HCl) 1.18 and 0.088 moleC₄H₈O₂ and 3.59% water.

Intermediates

[0314] a)(R)-6-Chloro-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0315] To a solution of 1.94 g (8.75 mol)(R)-6-chloro-4-methyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene in 20 mldichloromethane was added successively 2.3 g (10.5 mmol) ditert-butyldicarbonate and 53.5 mg (0.44 mmol) N,N-dimethylaminopyridine. After 3 hthe solvent was removed on a rotary evaporator and the residue waspurified by chromatography over silica gel (0.032-0.063 mm) withn-hexane: ethyl acetate (7: 1) as eluant to afford the desired compoundas a yellow oil (97.6%).

[0316] ISP-MS: m/e=322.3 ([M+H⁺])

[0317] b)(4R,9aR)-6-Chloro-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0318] To a solution of 0.65 g (2.0 mmol)(R)-6-chloro-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 10 ml acetic acid was added 0.64 g (10.1 mmol)sodium cyano borohydride. After 3 h the reaction mixture was poured into10% aqueous sodium carbonate solution and extracted twice with ethylacetate. The organic layers were washed with brine, dried over magnesiumsulfate, filtered and evaporated. The residue was purified bychromatography over silica gel (0.032-0.063 mm) with n-hexane: ethylacetate (4:1) as eluant to afford the desired compound as a colorlessoil (65.7%).

[0319] ISP-MS: m/e=324.3 ([M+H⁺])

Example 3

[0320] a)(4R,9aS)-6-Chloro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;Hydrochloride

[0321] To a solution of 1.0 g (4.27 mmol)(R)-6-chloro-4-methyl-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one(Example 1, intermediate b) in 30 ml methanol was added 0.62 g (25.5mmol) magnesium turnings. After a few minutes gas production began.Temperature was kept at ambient temperature with a cooling bath. After2.5 h the reaction mixture was poured into a mixture of 60 ml 1Nhydrochloric acid, ice and 90 ml buffer pH 7 and was extracted twicewith ethyl acetate. The organic phases were washed with brine, driedover magnesium sulfate and filtered. After evaporation of the solventthe remaining light brown oil (350 mg) was dissolved in 20 ml tert-butylmethyl ether, 0.25 g (6.60 mmol). To the solution was added lithiumaluminium hydride and the reaction mixture was heated to reflux for 1 h.The oil bath was removed and the mixture was cooled to room temperature.The suspension was poured into 7 ml saturated aqueous potassium sodiumtartrate solution and filtered over dicalite speed plus. The filtratewas extracted twice with ethyl acetate. The combined organic phases werewashed with brine, dried over magnesium sulfate and filtered. The crudeproduct was purified by column chromatography over silica gel(0.032-0.063 mm) with dichloromethane: methanol (49: 1) as eluant. Thecolorless oil (28 mg) was dissolved in 2 ml ethyl acetate and 0.1 ml ofa 2M hydrochloric acid solution in ethyl acetate was added. Theresulting suspension was stirred at 0 deg C. for 45 min and filtered.The filter-cake was washed with ethyl acetate and dried under highvacuum to afford the desired compound as a colorless powder (2.1 %).

[0322] ISP-MS: m/e=224.1 ([M+H⁺])

Example 4

[0323] (R)-6-Bromo-4-methyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;Hydrochloride

[0324] This compound was prepared in analogy to Example 1 from(R)-6-bromo-4-methyl-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one.

[0325] Light yellow crystals (45.4%).

[0326] ISP-MS: m/e=266.2 ([M+H⁺])

Intermediates

[0327] a) Pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester

[0328] To a solution of 80.9 g (0.43 mol)1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in 1800 mlacetonitrile was added 111.4 g (0.51 mol) di-tert-butyl dicarbonatefollowed by 2.60 g (0.02 mol) 4-dimethylaminopyridine. After 1 h thesolvent was removed on a rotary evaporator and the residue was purifiedby flash column chromatography over silica gel (0.032-0.063 mm) withn-hexane: ethyl acetate (9: 1) as eluant to afford the product as ayellow oil (96.6%).

[0329] ISP-MS: m/e=291.2 ([M+H⁺])

[0330] b) 7-Oxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid1-tert-butyl Ester 2-ethyl Ester

[0331] To a solution of 88.7 g (0.31 mol)pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethylester in 1600 ml dichloromethane was added 150.5 g (0.61 mol)3-chloroperoxybenzoic acid. After 7 h another 150.5 g (0.61 mol)3-chloroperoxybenzoic acid was added. After 24 h the reaction mixturewas poured into 960 ml saturated aqueous potassium carbonate solution.Water and dichloromethane (1750 ml, 1: 1) were added, after 5 min theaqueous phase was separated and extracted three times each with 900 mldichloromethane. The combined organic phases were washed with 1000 mlwater and 1000 ml brine, dried over magnesium sulfate and filtered. Thesolvent was removed on a rotary evaporator until a white suspension hadformed. A 150 ml portion of tert-butyl methyl ether was added and thesuspension was filtered. The filter-cake was washed with 70 mltert-butyl methyl ether and dried under high vacuum to afford thedesired product as a white solid (59.5%).

[0332] EI-MS: m/e306.2 ([M])

[0333] c) 6-Bromo-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic Acid1-tert-butyl Ester 2-ethyl Ester

[0334] To a suspension of 30.0 g (0.098 mol)7-oxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester in toluene were added simultaneously solutions of 20.5 ml(15.8 g, 0.098 mol) hexamethyldisilazane in 420 ml toluene and 29.4 ml(45.3 g, 0.24 mol) benzoyl bromide in 420 ml toluene over 1 h. After anadditional hour the reaction mixture was poured into 400 ml 10% aqueoussodium carbonate solution and the phases were separated. The aqueousphase was extracted twice with 500 ml ethyl acetate and the combinedorganic layers washed twice with 600 ml saturated sodium carbonatesolution and brine. After filtration and removal of the solvent theresidue was purified by chromatography over silica gel (0.032-0.063 mm)with n-hexane: ethyl acetate (24:1 then 19:1) as eluant to afford theproduct as a colorless solid (50.9%).

[0335] ISP-MS: m/e=371.1 ([M+H⁺])

[0336] d) 6-Bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic Acid EthylEster

[0337] The solution of 18.4 g (0.05 mol)6-bromo-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester in 165 ml dichloromethane was cooled to 0 deg C. and then38.0 ml trifluoroacetic acid was added within 5 min. The cooling bathwas removed and after 2 h at room temperature the reaction mixture waspoured into 500 ml saturated aqueous sodium bicarbonate solution. Theorganic layer was extracted three times with 150 ml dichloromethane. Thecombined organic phases were washed with 200 ml brine, dried overmagnesium sulfate and filtered. The solvent was evaporated and theresidue was dried under high vacuum to afford 12.0 g (95.5%) of thedesired product as a colorless solid.

[0338] ISP-MS: m/e=269.2 ([M+H⁺])

[0339] e)(R)-6-Bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic Acid Ethyl Ester

[0340] This compound was prepared in analogy to Example 1, intermediatea) from 6-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester,potassium tert-butoxide and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

[0341] Yellow gum (93.2%).

[0342] ISP-MS: m/e=426.3 ([M+H⁺])

[0343] f)(R)-6-Bromo-4-methyl-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one

[0344] This compound was prepared in analogy to Example 1, intermediateb) from(R)-6-bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid ethyl ester.

[0345] Colorless solid (73.6%).

[0346] ISP-MS: m/e=282.0 ([M+H⁺])

Example 5

[0347](4R,9aR)-6-Bromo-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;Hydrochloride

[0348] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0349] Light brown solid (37.1%).

[0350] ISP-MS: 268.2 ([M+H⁺])

[0351] Elemental analysis: C₁₁H₁₅BrClN₃(304.619) calc.: C 43.37 H 4.96 N13.79 Cl 11.64 Br 26.23 found#): C 43.28 H 4.98 N 13.45Cl11.67 Br 26.00#) Calculated with 0.51% water

Intermediates

[0352] a)(R)-6-Bromo-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylicAcid tert-butyl Ester

[0353] This compound was prepared in analogy to Example 2, intermediatea) from (R)-6-bromo-4-methyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene,4-(dimethylamino)pyridine and di tert-butyl dicarbonate.

[0354] Light yellow foam (97.3%).

[0355] ISP-MS: m/e=366.1 ([M+H⁺])

[0356] b)(4R,9aR)-6-Bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicAcid Tert-butyl Ester

[0357] This compound was prepared in analogy to Example 2, intermediateb) from(R)-6-bromo-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester and sodium cyano borohydride.

[0358] Colorless solid (82.5%).

[0359] ISP-MS: m/e370.3 ([M+H⁺])

Example 6

[0360](4R,9aS)-6-Bromo-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;Hydrochloride

[0361] This compound was prepared in analogy to Example 2 from(4R,9aS)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0362] Colorless solid (77.8%).

[0363] ISP-MS: m/e=270.2 ([M+H⁺])

[0364] Elemental analysis: C₁₁H₁₅BrClN₃ (304.619) calc.#): C 43.55 H5.01 N 13.73 Cl 11.59 Br 26.12 found: C 43.37 H 4.85 N 13.57 Cl 11.57 Br25.87 #) Calculated with 1 mole C₁₁H₁₅BrClN₃ and 0.0154 mole C₆H₁₄ and0.07% water

Intermediate

[0365](4R,9aS)-6-Bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicAcid tert-butyl Ester

[0366] This compound was prepared in analogy to Example 2, intermediateb) from(R)-6-bromo-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester and sodium cyano borohydride.

[0367] Colorless solid (6.2%).

[0368] ISP-MS: m/e=370.3 ([M+H⁺])

Example 7

[0369] (R)-4,6-Dimethyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;Hydrochloride

[0370] This compound was prepared in analogy to Example 2 from(R)-4,6-dimethyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acidtert-butyl ester.

[0371] Light yellow solid (57.0%).

[0372] ISP-MS: m/e=204.2 ([M+H⁺])

Intermediate

[0373](R)-4,6-Dimethyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic AcidTert-butyl Ester

[0374] To a solution of 0.20 g (0.55 mmol)(R)-6-bromo-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate a) in 10 ml1,2-dimethoxyethane was added 63 mg (55 μmol)tetrakis(triphenylphosphine) palladium. After 30 min, 5 ml saturatedaqueous sodium carbonate solution and 0.09 ml (0.65 mmol) of a 1Mtrimethylboroxine solution in THF were added and the resultingsuspension was heated to reflux for 5 h. The reaction mixture was cooledto room temperature, poured into 20 ml 1M aqueous sodium hydroxidesolution and extracted three times with ethyl acetate. The combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered and evaporated. The residue was purified by flash columnchromatography on silica gel (0.032-0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant to yield the desired product as a yellow solid(71.1%).

[0375] ISP-MS: m/e=302.3 ([M+H⁺])

Example 8

[0376](4R,9aR)-4,6-Dimethyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;Hydrochloride

[0377] This compound was prepared in analogy to Example 2 from(4R,9aR)-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0378] Light yellow solid (75.9%).

[0379] ISP-MS: m/e=204.2 ([M+H⁺])

Intermediate

[0380](4R,9aR)-4,6-Dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicAcid Tert-butyl Ester

[0381] To a solution of 19.5 g (0.053 mol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) in 800 ml1,2-dimethoxyethane was added 12.2 g (0.01 mol)tetrakis(triphenylphosphine)palladium(0) and the suspension was stirredfor 30 min at room temperature. Water (400 ml), 16.8 g (0.16 mol) sodiumcarbonate and 13.3 g (0.10 mol) trimethylboroxine were added and thereaction mixture was heated to reflux and stirred for 3 h under reflux.The suspension was poured into 10% aqueous sodium bicarbonate solutionand ethyl acetate and the phases were separated. The organic layer waswashed with brine, dried over magnesium sulfate, filtered andevaporated. The residue was purified by chromatography on silica gel(0.032-0.063 mm) with n-hexane ethyl acetate (4: 1) as eluant to affordthe compound as a light yellow oil (52.6%). ISP-MS: m/e304.3 ([M+H⁺])

Example 9

[0382](4R,9aR)-6-Ethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;Hydrochloride

[0383] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-ethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0384] Off-white solid (94.5%).

[0385] ISP-MS: m/e=218.3 ([M+H⁺])

Intermediate

[0386](4R,9aR)-6-Ethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicAcid Tert-butyl Ester

[0387] To a solution of 0.70 g (1.90 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) in 14 mlN,N-dimethylformamide was added 73.0 mg[1,1′-bis(diphenyphosphino)ferrocene]-dichloropalladium(II) and after 15min, 4.8 ml of a 1M triethylborane solution in THF and 0.79 g (5.70mmol) potassium carbonate were added. After 4 h another 2.4 mltriethylborane solution was added and the reaction mixture stirredovernight at 65 deg C. The mixture was cooled to room temperature andthe suspension was poured into water and extracted twice with ethylacetate. The combined organic phases were washed with brine, dried overmagnesium sulfate, filtered and evaporated. The crude product waspurified by column chromatography on silica gel (Q.032-0.063 mm) withtert-butyl methyl ether: n-hexane (1:4) as eluant to yield the productas a colorless oil (89.5%).

[0388] ISP-MS: m/e=318.4 ([M+H⁺])

Example 10

[0389](4R,9aR)-4-Methyl-6-trifluoromethyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;hydrochloride

[0390] This compound was prepared in analogy to Example 2 from(4R,9aR)-4-methyl-6-trifluoromethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0391] Light brown solid (73.0%).

[0392] ISP-MS: m/e=258.2 ([M+H⁺])

Intermediate

[0393](4R,9aR)-4-Methyl-6-trifluoromethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0394] To a solution of 0.8 g (2.17 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) in 12 ml1-methyl-2-pyrrolidone, 2.36 g (17.4 mmol) sodium trifluoroacetate wasadded. After a solution had formed, 1.65 g (8.7 mmol) copper iodide wasadded and the reaction mixture was heated to 180 deg C. for 2 h. Themixture was cooled to room temperature, ethyl acetate and water wereadded and the suspension was filtered through a bed of dicalite speedplus. The phases were separated, the aqueous layer was washed with ethylacetate and the combined organic phases were washed with brine, driedover magnesium sulfate, filtered and evaporated. The residue waspurified by chromatography over silica gel (0.032-0.063 mm) withtert-butyl methyl ether: n-hexane (1: 5) as eluant to afford the desiredcompound as a colorless oil (27.7%).

[0395] ISP-MS: m/e=358.3 ([M+H⁺])

Example 11

[0396](4R,9aR)-6-Cyclopropyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;hydrochloride

[0397] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-cyclopropyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0398] Light brown solid (62.0%).

[0399] ISP-MS: m/e=230.3 ([M+H⁺])

Intermediate

[0400](4R,9aR)-6-Cyclopropyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0401] A suspension of 150.0 mg (1.23 mmol) 9-borabicyclo[3.3.1]nonaneand 47 μl (0.62 mmol) propargyl bromide in 1 ml tetrahydrofuran washeated to reflux for 2 h. The mixture was cooled to room temperaturethen 0.61 ml (1.83 mmol) of a degassed 3M sodium hydroxide solution wasadded and after 1 h a mixture of 0.20 g (0.54 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) and 19.0 mgtetrakis(triphenylphosphine)palladium in 1 ml tetrahydrofuran was added.The mixture was heated to reflux for 16 h then cooled to roomtemperature and poured into water and ethyl acetate; the phases wereseparated. The aqueous phase was extracted three times with ethylacetate and the combined organic layers were washed with 1M aqueoussodium hydroxide solution and brine, dried over magnesium sulfate,filtered and evaporated. The residue was purified by chromatography onsilica gel (0.032-0.063 mm) with n-hexane as eluant to afford thedesired product as a colorless oil (35.2%).

[0402] ISP-MS: m/e=330.4 ([M+H⁺])

Example 12

[0403](4R,9aR)-3-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-acrylicacid ethyl ester; hydrochloride

[0404] This compound was prepared in analogy to Example 2 from (4R9aR)-6-(2-ethoxycarbonyl-vinyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0405] Yellow solid (66.5%).

[0406] ISP-MS: m/e288.3 ([M+H⁺])

Intermediate

[0407](4R,9aR)-6-(2-Ethoxycarbonyl-vinyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0408] To a solution of 1.0 g (2.71 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) and 0.36 ml (3.25mmol) ethyl acrylate in 30 ml toluene were added 0.67 g (8.15 mmol)sodium acetate, 82.6 mg (0.27 mmol) tri(o-tolyl)phosphine and 0.04 mg(0.1 mmol) allylpalladium chloride dimer. The reaction mixture washeated under reflux for 20 h, then poured into saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate. The organic phasewas washed with 10% aqueous citric acid solution and brine, dried overmagnesium sulfate, filtered and evaporated. The crude product waspurified by column chromatography on silica gel (0.032-0.063 mm) withn-hexane:ethyl acetate (9: 1) as eluant to afford the desired compoundas a yellow solid (91.2%).

[0409] ISP-MS: m/e=388.3 ([M+H⁺])

Example 13

[0410](4R,9aR)-6-(3-Methoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0411] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(3-methoxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0412] Light brown oil (90.5%).

[0413] ISP-MS: m/e=262.3 ([M+H⁺])

Intermediate

[0414] a)(4R,9aR)-6-(3-Hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0415] To a solution of 245.0 mg (0.63 mmol)(4R,9aR)-6-(2-ethoxycarbonyl-vinyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 12, intermediate) in 10 ml diethyl etherwere added 50.0 mg (1.32 mmol) lithium aluminium hydride. After 2 h thereaction mixture was poured into saturated aqueous potassium sodiumtartrate solution and ethyl acetate then filtered through a short pad ofdicalite speed plus. The aqueous phase was extracted four times withethyl acetate and the combined organic layers were washed with brine,dried over magnesium sulfate, filtered and evaporated. The residue waspurified by chromatography on silica gel (0.032-0.063 mm) with ethylacetate: n-hexane as eluant to afford the compound as a colorless solid(50.5%).

[0416] ISP-MS: m/e=348.6 ([M+H⁺])

[0417] b)(4R,9aR)-6-(3-Methoxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0418] A solution of 160.0 mg (0.46 mmol)(4R,9aR)-6-(3-hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 4 ml tetrahydrofuran was cooled to 0 deg C. andtreated with 24.0 mg (0.51 mmol, 60% dispersion in mineral oil) sodiumhydride. After 30 min 32 μl (0.51 mmol) methyl iodide was added and thecooling bath was removed. After 6 h another 0.64 μl (1.02 mmol) methyliodide was added and the reaction was stirred overnight. The reactionmixture was poured into water and was extracted three times with ethylacetate. The combined organic layers were washed with brine, dried overmagnesium sulfate, filtered and concentrated on a rotary evaporator. Theresidue was purified by chromatography on silica gel (0.032-0.063 mm)with ethyl acetate: n-hexane (1:4) as eluant to afford the desiredcompound as a colorless oil (73.9%).

[0419] ISP-MS: m/e362.4 ([M+H⁺])

Example 14

[0420](4R,9aR)-4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene-6-carbonitrile;hydrochloride

[0421] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-cyano-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0422] Light yellow solid (62.3%).

[0423] ISP-MS: m/e=215.4 ([M+H⁺])

Intermediate

[0424](4R,9aR)-6-Cyano-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0425] To a solution of 0.20 g (0.54 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) in 5 ml dioxane wereadded 195.0 mg (2.17 mmol) copper(I) cyanide, 22.5 mg (22 μmol)tris(dibenzylideneacetone)dipalladium(0), 48.2 mg (87 μmol)1,1′-bis(diphenylphosphino)ferrocene and 0.13 g (0.81 mmol)tetraethylammonium cyanide and the suspension was heated to reflux andstirred for 1.5 h. The mixture was cooled to room temperature, filteredand the filtrate was washed successively with aqueous saturated sodiumbicarbonate solution, aqueous 10% citric acid solution, brine, driedover magnesium sulfate, filtered and evaporated. The residue wasimmediately purified by flash column chromatography on silica gel(0.032-0.063 mm) to afford the desired compound as a colorless foam(98.4%).

[0426] ISP-MS: m/e=315.3 ([M+H⁺])

Example 15

[0427](4R,9aR)-6-Cyclopropylmethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;hydrochloride

[0428] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-cyclopropylmethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0429] Light yellow crystals (89.6%).

[0430] ISP-MS: m/e=274.4 ([M+H⁺])

Intermediates

[0431] a)(4R,9aR)-4-Methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2,6-dicarboxylicacid 2-tert-butyl ester 6-methyl ester

[0432] To a solution of 6.0 g (16.3 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) in 60 ml methanol wereadded 0.57 g (0.8 mmol) and 3.4 ml (2.5 g, 24.4 mmol) triethylamine andthe reaction mixture was stirred at 80 deg C. for 24 h under a carbonmonoxide atmosphere of 40 bar. The suspension was cooled to roomtemperature, poured into a mixture of water, ethyl acetate and brine andwas extracted with further portions of ethyl acetate. The combinedorganic layers were separated, dried over magnesium sulfate andfiltered. The residue was purified by chromatography on silica gel(0.032-0.063 mm) to afford the product as a light yellow foam (74.4%).

[0433] ISP-MS: m/e=348.5 ([M+H⁺])

[0434] b)(4R,9aR)-6-Hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0435] A solution of 4.2 g (12.1 mmol)(4R,9aR)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2,6-dicarboxylicacid 2-tert-butyl ester 6-methyl ester in 100 ml tetrahydrofuran wascooled to 0 deg C. and treated dropwise with 48.4 ml diisobutylaluminiumhydride (48.4 mmol; 1M solution in THF). The cooling bath was removedand after 1 h at room temperature the reaction was quenched with a 10%aqueous potassium sodium tartrate solution and ethyl acetate was added.The two-phase system was filtered through a bed of dicalite speed plus;the filtrate was extracted with ethyl acetate and the organic phase wasdried over magnesium sulfate. After filtration and evaporation theresidue was purified by chromatography on silica gel (0.032-0.062 mm)with ethyl acetate as eluant to afford the desired product as a lightyellow foam (67.3%).

[0436] ISP-MS: m/e=320.4 ([M+H⁺])

[0437] c)(4R,9aR)-6-Cyclopropylmethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0438] To a solution of 1.2 g (37.6 mmol)(4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 30 ml N,N-dimethylformamide was added 0.18 g(41.4 mmol) sodium hydride. After 30 min 0.72 ml (1.01 g, 75.2 mmol)(bromomethyl)cyclopropane was added and the reaction was stirred for 3h. The reaction mixture was poured into 10% aqueous sodium bicarbonatesolution and ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, filtered and evaporated. The residue waspurified by chromatography on silica gel (0.032-0.063 mm) with agradient of ethyl acetate:n-hexane (1;1 to 100: 0) as eluant to affordthe compound as a light yellow oil (67.1%).

[0439] ISP-MS: m/e=374.5 ([M+H⁺])

Example 16

[0440](4R,9aR)-6-(2-Methoxy-ethoxymethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0441] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(2-methoxy-ethoxymethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0442] EI-MS: m/e=278.3 ([M+H⁺])

Intermediate

[0443](4R,9aR)-6-(2-Methoxy-ethoxymethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0444] This compound was prepared in analogy to Example 15 intermediatec), from(4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, sodium hydride and 2-bromoethyl methyl ether.

[0445] Colorless oil (33.8%).

[0446] ISP-MS: m/e=378.5 ([M+H⁺])

Example 17

[0447](4R,9aR)-6-Methoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0448] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-methoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0449] Light yellow oil (95.3%).

[0450] ISP-MS: m/e234.4 ([M+H⁺])

Intermediate

[0451](4R,9aR)-6-Methoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0452] This compound was prepared in analogy to Example 15 intermediatec), from(4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester and methyl iodide.

[0453] Light yellow oil (75.8%).

[0454] ISP-MS: m/e334.4 ([M+H⁺])

Example 18

[0455] (R)-4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;hydrochloride 1:1.45

[0456] This compound was prepared in analogy to Example 2 from(R)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0457] Colorless solid (51.7%).

[0458] EI-MS: m/e=189.2 ([M])

[0459] Elemental analysis: C₁₁H₁₄ClN₁₃.1.45HCl (242.130) calc.: C 54.57H 6.85 N 17.36 Cl 21.23 found*: C 54.63 H 6.61 N 17.41 Cl 21.38 #)Calculated with 0.48% water

Intermediates

[0460] a) (R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester

[0461] This compound was prepared in analogy to Example 1 intermediatea), from 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester,potassium tert-butoxide and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

[0462] Yellow oil (100%).

[0463] ISP-MS: m/e=348.4 ([M+H⁺])

[0464] b) (R)-4-Methyl-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one

[0465] This compound was prepared in analogy to Example 1 intermediateb), from (R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylic acid ethyl ester.

[0466] Colorless solid (70.2%).

[0467] EI-MS: m/e=201.1 ([M])

[0468] c) (R)-4-Methyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene

[0469] This compound was prepared in analogy to Example 1 from(R)-4-methyl-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one.

[0470] Pale yellow oil (79%).

[0471] ISP-MS: m/e=188.3 ([M+H⁺])

[0472] d)(R)-4-Methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acidtert-butyl ester

[0473] This compound was prepared in analogy to Example 2 intermediatea), from (R)-4-methyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene,4-(dimethylamino)pyridine and di tert-butyl dicarbonate.

[0474] Yellow oil (96.1%).

[0475] EI-MS: m/e=287.3 ([M])

[0476] e)(R)-4-Methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0477] This compound was prepared in analogy to Example 2 intermediateb), from (R)-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester and sodium cyano borohydride.

[0478] Light brown oil (83.4%).

[0479] ISP-MS: m/e=290.3 ([M+H⁺])

Example 19

[0480](4R,9aR)-4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylamine

[0481] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-amino-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0482] White foam (78.2%).

[0483] EI-MS: m/e=205.2 ([M+H⁺])

Intermediates

[0484] a)(4R,9aR)-6-(Benzhydrylidene-amino)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0485] A mixture consisting of 0.20 g (0.54 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, 91 μl (0.54 mmol) benzophenone imine, 73.0 mg(0.76 mmol) sodium tert-butoxide, 5.6 mg (0.01 mmol)tris(dibenzylideneacet6ne)dipalladium chloroform complex and 10.1 mg(0.02 mmol) R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene in 3 mltoluene was stirred at reflux for 1 h. The reaction mixture was cooledto room temperature, poured into 10% aqueous sodium bicarbonate solutionand extracted twice with ethyl acetate. The combined organic layers werewashed with brine, dried over magnesium sulfate, filtered andevaporated. The residue was purified by chromatography on silica gel(0.032-0.063 mm) with n-hexane : ethyl acetate (2: 1) as eluant toafford the product as a yellow foam (94.3%).

[0486] ISP-MS: m/e=469.3 ([M+H⁺])

[0487] b)(4R,9aR)-6-Amino-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0488] To a solution of 0.23 g (0.49 mmol)(4R,9aR)-6-(benzhydrylidene-amino)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 2.5 ml methanol were added 0.46 g (7.4 mmol)ammonium formate and 104 mg (0.05 mmol) 5% palladium on charcoal and thesuspension was stirred for 1 h at 60 deg C. The cooled reaction mixturewas filtered through a short bed of dicalite speed plus, extracted with10% aqueous sodium bicarbonate, brine, dried over magnesium sulfate,filtered and evaporated. The residue was purified by chromatography onsilica gel (0.032-0.063 mm) to yield the product as a colorless oil(58.9%).

[0489] ISP-MS: m/e=305.3 ([M+H⁺])

Example 20

[0490](R)-6-Chloro-4,9-dimethyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;hydrochloride

[0491] A solution of 0.25 g (0.71 mmol)(R)-6-chloro-9-formyl-4-methyl-3,4-dihy4ro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 5 ml dichloromethane was cooled to 0 deg C.Trifluoroacetic acid (5.0 ml) and, after 5 min, 0.68 ml (4.30 mmol)triethyl silane were added. The cooling bath was removed and after 7 hat room temperature the solution was poured into saturated aqueoussodium bicarbonate solution and was extracted four times withdichloromethane. The combined organic layers were washed with brine,dried over magnesium sulfate, filtered and evaporated. The residue waspurified by chromatography on silica gel (0.032-0.063 mm) withdichloromethane: methanol: ammonia (49:1:0.1) as eluant. The resultingoil was dissolved in 5 ml ethyl acetate and treated dropwise with 0.22ml of a 2.1M hydrochloric acid solution in ethyl acetate. The suspensionwas filtered; the filter-cake was washed with ethyl acetate and driedunder high vacuum to afford the compound as a colorless solid (69.4%).

[0492] ISP-MS: m/e=236.2 ([M+H⁺])

[0493] Elemental analysis: C₁₂H₁₅Cl₂N₃ (272.179) calc.: C 52.95 H 5.56 N15.44 Cl 26.05 found*): C 53.20 H 5.71 N 15.19 Cl 25.82 #) Calculatedwith 0.46% water.

Intermediate

[0494](R)-6-Chloro-9-formyl-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0495] N,N-Dimethylformamide (10 ml) was cooled to 1 deg C. and treateddropwise with 5.1 ml (56.0 mmol) phosphorus oxychloride. After theaddition the temperature was again cooled to 1 deg C. and a solution of1.0 g (3.11 mmol)(R)-6-chloro-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 2, intermediate a) in 10 mlN,N-dimethylformamide was added. The cooling bath was removed and after1.5 h at room temperature the reaction mixture was poured into saturatedaqueous sodium bicarbonate solution and was extracted three times withethyl acetate. The combined organic phases were washed with water andbrine, dried over magnesium sulfate, filtered and evaporated. Theresidue was purified by chromatography on silica gel (0.032-0.063 mm)with ethyl acetate: n-hexane (1: 3) as eluant to yield the desiredcompound as a yellow foam (55.2%).

[0496] ISP-MS: m/e=350.3 ([M+H⁺])

Example 21

[0497](4R,9aR)-6-Benzyloxy-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0498] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-benzyloxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0499] Colorless oil (93.7%).

[0500] ISP-MS: m/e=296.4 ([M+H⁺])

Intermediate

[0501](4R,9aR)-6-Benzyloxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0502] To a solution of 3.0 g (8.15 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) in 30 ml toluene wasadded 0.20 g (0.29 mmol)(S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl and 0.12 g (0.12mmol) di-palladium-tris(dibenzylideneacetone) chloroform complex. After30 min, 1.0 ml (1.06 g, 9.80 mmol) benzylalcohol and 0.70 g (16.0 mmol)sodium hydride (55-65% dispersion in oil) were added and the reactionmixture was stirred for 3.5 h at 70 deg C. After cooling to roomtemperature, the reaction mixture was poured onto 10% aqueous sodiumcarbonate solution and extracted three times with ethyl acetate. Thecombined organic phases were washed with brine, dried over magnesiumsulfate and filtered. After evaporation of the volatile components, theresidue was chromatographed on silica gel (0.032-0.063 mm) with ethylacetate: n-hexane (1:4) as eluant.

[0503] Yellow oil (62.0%).

[0504] ISP-MS: m/e=396.4 ([M+H⁺])

Example 22

[0505](4R,9aR)-6-Methoxy-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0506] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-methoxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0507] Colorless solid (95.4%).

[0508] ISP-MS: m/e=220.4 ([M+H⁺])

Intermediates

[0509] a)(4R,9aR)-6-Hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0510] To a solution of 3.90 g (9.86 mmol)(4R,9aR)-6-benzyloxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 21, intermediate) in 30 ml methanol:ethyl acetate (1:1 v/v) 0.20 g 10% palladium on charcoal was added andthe reaction was hydrogenated at atmospheric pressure for 2 h. Afterfiltration over dicalite speed plus the filtrate was evaporated and theresidue was chromatographed on silica gel (0.032-0.063 mm) with ethylacetate: n-hexane (1: 1) as eluant to afford the desired compound as acolorless foam (82.0%).

[0511] ISP-MS: m/e=306.4 ([M+H⁺])

[0512] b)(4R,9aR)-6-Methoxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0513] To a solution of 0.25 g (0.82 mmol)(4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 2 ml N,N-dimethylformamide, 40 mg (0.90 mmol)sodium hydride (55-65% dispersion in oil) was added. After 30 min, 0.10ml (0.23 g, 1.64 mmol) methyl iodide was added. After 1 h the reactionmixture was poured onto water and extracted three times with ethylacetate. The organic layers were washed twice with water, then brine andwere dried over magnesium sulfate. After filtration and evaporation ofthe solvent the product was purified by column chromatography on silicagel (0.032-0.063 mm) with ethyl acetate:n-hexane (1:5) as eluant.

[0514] Colorless oil (80.3%).

[0515] ISP-M$: m/e=320.4 ([M+H⁺])

Example 23

[0516](4R,9aR)-6-Ethoxy-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0517] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-ethoxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0518] Light yellow oil (87.8%).

[0519] ISP-MS: m/e=234.4 ([M+H⁺])

Intermediate

[0520](4R,9aR)-6-Ethoxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0521] This compound was prepared in analogy to Example 22 intermediateb), from(4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, sodium hydride and ethyl bromide.

[0522] Colorless oil (64.6%).

[0523] ISP-MS: m/e=334.3 ([M+H⁺])

Example 24

[0524](4R,9aR)-2-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yloxy)-ethanol

[0525] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(2-hydroxy-ethoxy)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0526] Light brown solid (84.1%).

[0527] ISP-MS: m/e=250.3 ([M+H⁺])

Intermediate

[0528](4R,9aR)-6-(2-Hydroxy-ethoxy)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0529] This compound was prepared in analogy to Example 22 intermediateb), from(4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, sodium hydride and 2-bromoethanol.

[0530] Colorless oil (48.9%).

[0531] ISP-MS: m/e=350.5 ([M+H⁺])

Example 25

[0532](4R,9aR)-6-(2-Methoxy-ethoxy)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0533] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(2-methoxy-ethoxy)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0534] Light brown oil (97.3%).

[0535] ISP-MS: m/e=264.3 ([M+H⁺])

Intermediate

[0536](4R,9aR)-6-(2-Methoxy-ethoxy)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0537] This compound was prepared in analogy to Example 22 intermediateb), from(4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, sodium hydride and 2-bromoethyl methyl ether.

[0538] Colorless oil (72.3%).

[0539] ISP-MS: m/e=364.3 ([M+H⁺])

Example 26

[0540](4R,9aR)-6-Cyclobutylmethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0541] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-cyclobutylmethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0542] Yellow oil (78.8%).

[0543] ISP-MS: m/e=288.3 ([M+H⁺])

Intermediate

[0544](4R,9aR)-6-Cyclobutylmethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0545] This compound was prepared in analogy to Example 15 intermediatec), from

[0546](4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, sodium hydride and (bromomethyl)cyclobutane.

[0547] Light yellow oil (16.2%).

[0548] ISP-MS: m/e=388.4 ([M+H⁺])

Example 27

[0549](4R,9aR)-6-Ethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0550] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-ethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0551] Yellow oil (93.6%).

[0552] ISP-MS: m/e=248.3 ([M+H⁺])

Intermediate

[0553](4R,9aR)-6-Ethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0554] This compound was prepared in analogy to Example 15 intermediatec), from(4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, sodium hydride and ethyl bromide.

[0555] Light yellow oil (69.6%).

[0556] ISP-MS: m/e=348.5 ([M+H⁺])

Example 28

[0557](4R,9aR)-6-Cyclohexylmethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0558] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-cyclohexylmethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0559] Yellow oil (45.5%).

[0560] ISP-MS: m/e=316.3 ([M+H⁺])

Intermediate

[0561](4R,9aR)-6-Cyclohexylmethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0562] This compound was prepared in analogy to Example 15 intermediatec), from(4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, sodium hydride and (bromomethyl)cyclohexane.

[0563] Light yellow oil (19.0%).

[0564] ISP-MS: m/e=416.4 ([M+H⁺])

Example 29

[0565](4R,9aR)-2-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethoxy)-ethanol

[0566] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(2-hydroxy-ethoxymethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0567] Light yellow oil (82.8%).

[0568] ISP-MS: m/e=264.2 ([M+H⁺])

Intermediates

[0569] a)(4R,9aR)-4-Methyl-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxymethyl]-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0570] This compound was prepared in analogy to Example 15 intermediatec), from(4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, sodium hydride and2-(2-bromoethoxy)tetrahydro-2H-pyran.

[0571] Light yellow oil (30.3%).

[0572] ISP-MS: m/e=448.5 ([M+H⁺])

[0573] b)(4R,9aR)-6-(2-Hydroxy-ethoxymethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0574] To the solution of 0.16 g (0.36 mmol)(4R,9aR)-4-methyl-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxymethyl]-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 3 ml methanol was added 0.136 g (0.71 mmol)para-toluenesulphonic acid. After 30 min, the solvent was removed on arotary evaporator and the residue was chromatographed on silica gel(0.032-0.063 mm) with dichloromethane:methanol:ammonia (19:1:0.1) aseluant to afford the desired compound as a light yellow oil (71.6%).

[0575] ISP-MS: m/e=364.2 ([M+H⁺])

Example 30

[0576](4R,9aR)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-methanol

[0577] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 15, intermediate b).

[0578] White solid (25.6%).

[0579] ISP-MS: m/e=220.4 ([M+H⁺])

Example 31

[0580](4R,9aR)-6-Isobutyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;hydrochloride

[0581] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-isobutyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0582] Colorless solid (62.5%).

[0583] ISP-MS: m/e=246.4 ([M+H⁺])

Intermediate

[0584](4R,9aR)-6-Isobutyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0585] To a solution of 2.0 g (5.43 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) in 50 ml1,2-dimethoxyethane 0.75 g (0.65 mmol) tetrakis(triphenylphosphine)palladium was added. After 20 min, 16.3 ml (16.3 mmol)triisobutylaluminium (1M solution in n-hexane) was added and thereaction mixture was heated under reflux for 66 h. After cooling to roomtemperature another 8.1 ml (8.1 mmol) triisobutylaluminium (1M solutionin n-hexane) was added and the reaction again heated under reflux. After5 h the reaction was poured onto 1M aqueous sodium hydroxide solutionand extracted three times with ethyl acetate. The combined organiclayers were washed with brine, dried over magnesium sulfate, filteredand evaporated. The residue was chromatographed on silica gel(0.032-0.063 mm) with ethyl acetate: n-hexane (1:3) as eluant to affordthe desired compound as a light brown oil (76.2%).

[0586] ISP-MS: m/e=346.4 ([M+H⁺])

Example 32

[0587](4R,9aR)-6-Difluoromethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0588] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-difluoromethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0589] Light brown oil (98.0%).

[0590] ISP-MS: m/e=240.4 ([M+H⁺])

Intermediates

[0591] a) (4R,9aR)-6-Formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester

[0592] A solution of 2.0 g (5.43 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) in 15 mltetrahydrofuran was cooled to −75 deg C. and treated with 4.40 ml (0.65mmol) tert-butyllithium (1.5 M solution in n-pentane). After 30 min,0.60 ml (0.63 g, 8.15 mmol) N,N-dimethylformamide was added dropwise.After 2.5 h the reaction mixture was poured onto 10% aqueous citric acidsolution and extracted three times with ethyl acetate. The combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered and evaporated. The residue was purified byflash-chromatography on silica gel (0.032-0.063 mm) with ethyl acetate:n-hexane (1:3) as eluant to afford the desired compound as a yellow oil(40.1%).

[0593] ISP-MS: m/e=319.5 ([M+H⁺])

[0594] b)(4R,9aR)-6-Difluoromethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0595] To a solution of 83.0 μl (0.10 g, 0.63 mmol) diethylaminosulphurtrifluoride in 3 ml dichlorormethane 0.20 g (0.63 mmol)(4R,9aR)-6-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester dissolved in 3 ml dichloromethane was added andthe reaction was stirred at room temperature for 5.5 h. After 1 h atreflux the reaction was poured onto water and extracted three times withethyl acetate. The combined organic layers were washed with water andbrine, dried over magnesium sulfate, filtered and evaporated. Theresidue was flash-chromatographed on silica gel (0.032-0.063 mm) withethyl acetate: n-hexane (1:2) as eluant to afford the desired compoundas a light brown oil (28.1%).

[0596] ISP-MS: m/e=340.3 ([M+H⁺])

Example 33

[0597](4R,9aR)-6-Fluoromethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0598] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-fluoromethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0599] Colorless oil (88.6%).

[0600] ISP-MS: m/e=222.3 ([M+H⁺])

Intermediate

[0601](4R,9aR)-6-Fluoromethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0602] A solution of 82.0 μl (0.11 g, 0.63 mmol) diethylaminosulphurtrifluoride in 2 ml dichloromethane was cooled to −78 deg C. and treatedwith a solution of 0.20 g (0.63 mmol)(4R,9aR)-6-(2-hydroxy-ethoxymethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 15, intermediate b) in 2 mldichloromethane. The cooling bath was removed and the reaction stirredfor 1 h at room temperature. The solution was extracted with 10% aqueoussodium bicarbonate solution, washed with brine, dried over magnesiumsulfate, filtered and evaporated. The residue was chromatographed onsilica gel (0.032-0.063 mm) with ethyl acetate: n-hexane (1:2) as eluantto afford the desired compound as a colorless oil (51.7%).

[0603] ISP-MS: m/e=322.4 ([M+H⁺])

Example 34

[0604](4R,9aR)-1-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethanone

[0605] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-acetyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0606] Yellow oil (93.9%).

[0607] ISP-MS: m/e=232.2 ([M+H⁺])

Intermediate

[0608](4R,9aR)-6-Acetyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

Procedure 1

[0609] The solution of 0.50 g (1.0 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) in 20 ml diethyl etherwas cooled to −100 deg C. and treated dropwise with 1.0 ml (1.5 mmol)tert-butyllithium (1.5 M solution in n-pentane). After 30 min, 0.14 mlN,N-dimethylacetamide was added and the reaction temperature was raisedto −75 deg C. After 30 min, the reaction was quenched with 10% aqueousammonium chloride solution and extracted twice with ethyl acetate. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered and evaporated. The residue was flash-chromatographedon silica gel (0.032-0.063 mm) with ethyl acetate: n-heptane (1:1) aseluant.

[0610] Yellow oil (55.4%).

[0611] ISP-MS: m/e=332.2 ([M+H⁺])

Procedure 2

[0612] To a solution of(4R,9aR)-6-(1-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 38, intermediate) (229 mg) in CH₂Cl₂ (4ml) was added MnO₂ (598 mg) under argon. The mixture was stirred at roomtemperature for 24 hours. Further MnO₂ (299 mg) was added and themixture was stirred for 2 days. The mixture was filtered through aCelite® pad, washing with CH₂Cl₂ and the filtrate was concentrated invacuo. The residue was purified by column chromatography [SiO₂;isohexane-ethyl acetate (4:1)]. A portion (15 mg) of the purifiedintermediate was deprotected according to the procedure described forExample 56 to afford(4R,9aR)-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethanonedi-trifluoroacetate (37 mg) as a yellow oil: HPLC [Xterra; 20/50; 235nm] 98.7%, 1.11 min; MS (ES) 231.0 (MH⁺).

Example 35

[0613](4R,9aR)-1-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propan-1-one

[0614](4R,9aR)-1-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propan-1-onedi-trifluoroacetate (40 mg) was made from6-(1-hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (190 mg) according to procedure 2 described inExample 34 to afford the product as a yellow oil: HPLC [Xterra; 20/50;220 nm] 98.0%,2.46 min; MS (ES) 245.0 (MH⁺).

Example 36

[0615](4R,9aR)-1-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-butan-1-one

[0616](4R,9aR)-1-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-butan-1-onedi-trifluoroacetate (35 mg) was made from6-(1-hydroxy-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (142 mg) according to procedure 2 described inExample 34 to afford the product as a yellow oil: HPLC [Xterra; 50/80;220 nm] 99.3%, 1.08 min; MS (ES) 259.0 (MH⁺).

Example 37

[0617](4R,9aR)-2,2,2-Trifluoro-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethanone

[0618] This compound was prepared in analogy to Example 2 from(4R,9aR)-4-methyl-6-trifluoroacetyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0619] Yellow solid (40.7%).

[0620] ISP-MS: m/e=304.3 ([M+Na⁺])

Intermediate

[0621](4R,9aR)-4-Methyl-6-trifluoroacetyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0622] To a solution of 0.30 g (0.86 mmol)(4R,9aR)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2,6-dicarboxylicacid 2-tert-butyl ester 6-methyl ester (Example 15, intermediate a) in 5ml toluene 0.16 ml (0.15 g, 1.08 mmol) (trifluoromethyl) trimethylsilanewas added. The solution was cooled to −75 deg C. and 22 μl (0.022 mmol)tetrabutylammonium fluoride (1M in tetrahydrofuran) was added. Thecooling bath was removed and after 2 h at room temperature the reactionwas poured onto 1M hydrochloric acid and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over magnesiumsulfate, filtered and evaporated. The residue was flash-chromatographedon silica gel (0.032-0.063 mm) with ethyl acetate: n-hexane (1:2) aseluant to afford the desired compound as a light yellow oil (23.7%).

Example 38

[0623](4R,9aR)-1-(RS)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethanol

[0624] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(1-(RS)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0625] Light brown oil (77.6%).

[0626] ISP-MS: m/e=234.3 (M+H⁺)

Intermediate

[0627](4R,9aR)-6-(1-(RS)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0628] A solution of 6.0 g (16.3 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 250 ml diethyl ether was cooled to −100 deg C.and treated with 11.9 ml (17.9 mmol) tert-butyllithium (1.5 M inn-pentane). After 15 min, 1.0 ml (0.79 g, 17.9 mmol) acetaldehyde wasadded and the reaction was stirred for 40 min at the same temperature.After warming to −75 deg C. the reaction mixture was poured onto 10%aqueous ammonium chloride solution and extracted three times with ethylacetate. The combined organic layers were washed with brine, dried overmagnesium sulfate, filtered and evaporated. The residue waschromatographed on silica gel (0.032-0.063 mm) with ethyl acetate:n-hexane (2: 3) as eluant to afford a first batch of compound. Theremaining product-containing fractions were pooled and chromatographedagain to yield a second batch of compound (56.9% total).

[0629] Light brown oil.

[0630] ISP-MS: m/e=334.3 (M+H⁺)

Examples 39 and 40

[0631](4R,9aR)-6-(1-(R)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluoreneand

[0632](4R,9aR)-6-(1-(S)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene

[0633] A solution of 3.09 g (9.27 mmol)(4R,9aR)-6-(1-(RS)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 38, intermediate) in 33 mldichloromethane was cooled to 0 deg C. and treated with 8.8 ml (12.7 g,0.11 mol) trifluoroacetic acid. The cooling bath was removed and thevolatile components were removed on a rotary evaporator. The residue waschromatographed on silica gel (0.032-0.063 mm) withdichloromethane:methanol:ammonia (19:1:0.1). The remaining oil wasdissolved in dichloromethane and saturated aqueous sodium bicarbonatesolution and extracted until all product was extracted from the aqueousphase. The combined organic layers were washed with brine, dried overmagnesium sulfate, filtered and evaporated. The remaining light brownoil was chromatographed on a Chiralpak-AD column with 7%ethanol/n-heptane yielding the two diastereomers, the R-diastereomerbeing eluted first.

Example 39

[0634](4R,9aR)-6-(1-(R)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro1H-2,4a,5-triaza-fluorene

[0635] Light brown solid (36.5%).

[0636] ISP-MS: m/e=234.2 (M+H⁺)

Example 40

[0637](4R,9aR)-6-(1-(S)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene

[0638] Light brown oil (38.4%).

[0639] ISP-MS: m/e=234.2 (M+H⁺)

Example 41

[0640](4R,9aR)-6-(1-(R)-Methoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0641] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(1-(R)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0642] Light yellow oil (87.8%).

[0643] ISP-MS: m/e=248.2 (M+H⁺)

Intermediates

[0644] a)(4R,9aR)-6-(1-(R)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0645] To a solution of 0.68 g (2.91 mmol)(4R,9aR)-6-(1-(R)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene(Example 39) in 5 ml dichloromethane were added 0.70 g (0.32 mmol)di-tert-butyldicarbonate and 17.8 mg (0.15 mmol)4-(dimethylamino)pyridine. After 1 h the solvent was evaporated and theresidue was chromatographed on silica gel (0.032-0.063 mm) with ethylacetate: n-heptane (1:2) as eluant.

[0646] Colorless foam (77.7%). ISP-MS: m/e =334.3 (M+H⁺)

[0647] b)(4R,9aR)-6-(1-(R)-Methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0648] To a solution of 0.75 g (2.25 mmol)(4R,9aR)-6-(1-(R)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 5 ml N,N-dimethylformamide was added 0.12 g(2.70 mmol) sodium hydride (55-65% dispersion in oil). After 30 min,0.28 ml (0.64 g, 4.50 mmol) methyl iodide was added and the reactionmixture was stirred at 50 deg C. for 2 h. After cooling to roomtemperature the reaction mixture, was poured onto 10% aqueous ammoniumchloride solution and extracted three times with ethyl acetate. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered and evaporated. The residue was chromatographed onsilica gel (0.032-0.063 mm) with ethyl acetate: n-heptane (1:2) aseluant.

[0649] Yellow oil (89.6%).

[0650] ISP-MS: m/e=348.4 (M+H⁺)

Example 42

[0651](4R,9aR)-6-(1-(S)-Methoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0652] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(1-(S)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0653] Light yellow oil (94.2%).

[0654] ISP-MS: m/e=248.2 (M+H⁺)

Intermediates

[0655] a)(4R,9aR)-6-(1-(S)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0656] This compound was prepared in analogy to Example 41 intermediatea), from(4R,9aR)-6-(1-(S)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene(Example 40), di-tert-butyldicarbonate and 4-(dimethylamino)pyridine.

[0657] Colorless foam (94.4%).

[0658] ISP-MS: m/e=334.3 (M+H⁺)

[0659] Alternatively, this compound was obtained in the following way:

[0660] To a stirred solution of (R)-Me-CBS-oxazaborolidine (770 μl, 1Min toluene) in THF (3 ml) was added borane-dimethylsulfide (770 μl, 2Min THF) at 0 ° C. under nitrogen. A solution was stirred for 5 mins,then6-acetyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 34, intermediate b) (255 mg) in THF (2.5ml) was added dropwise over 45 mins. A solution was stirred at 0° C. for3 hours, quenched with methanol and partitioned between aqueous ammoniumchloride and EtOAc. The phases were separated and the organic layer waswashed with brine, dried (MgSO₄) and concentrated in vacuo. The residuewas purified by column chromatography [SiO₂; isohexane-ethyl acetate(1:1)] to afford6-((1S)-1-hydroxy-ethyl)-(4R,9aR)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (185 mg) as a colorless oil: ¹H NMR (400 MHz,CDCl₃): 7.16 (1H, d, J 7 Hz), 6.35 (1H, d, J 7 Hz), 4.37-4.31 (1H, brs), 4.31-4.19 (1H, br s), 4.09-3.95 (1H, m), 3.95-3.85 (1H, m),3.13-2.94 (2H, m), 2.79-2.55 (1H, br s), 2.54 (1H, dd, J 6 and 16 Hz),1.48 (9H, s), 1.44 (3H, d, J 6.5 Hz) and 1.24 (3H, d, J 6.5 HZ); MS (ES)334.3 (MH⁺).

[0661] b)(4R,9aR)-6-(1-(S)-Methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0662] This compound was prepared in analogy to Example 41 intermediateb), from(4R,9aR)-6-(1-(S)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H--2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0663] Yellow oil (88.7%).

[0664] ISP-MS: m/e=348.4 (M+H⁺)

Example 43

[0665](4R,9aR)-6-(1-(R)-Ethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0666] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(1-(R)-ethoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, prepared in analogy to Example 41, intermediatesa) and b).

[0667] Light yellow oil (86.1%).

[0668] ISP-MS: m/e=262.2 (M+H⁺)

Example 44

[0669](4R,9aR)-6-(1-(R)-Cyclopropylmethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0670] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(1-(R)-cyclopropylmethoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, prepared in analogy to Example 41, intermediatesa) and b).

[0671] Light yellow oil (90.4%).

[0672] ISP-MS: m/e=288.2 (M+H⁺)

Example 45

[0673](4R,9aR)-6-(1-(S)-Ethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0674] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(1-(S)-ethoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester, prepared in analogy to Example 41, intermediatesa) and b).

[0675] Colorless oil (96.1%).

[0676] ISP-MS: m/e=262.2 (M+H⁺)

Example 46

[0677](4R,9aR)-6-(1-(S)-Cyclopropylmethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0678] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(1-(S)-cyclopropylmethoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, prepared inanalogy to Example 41, intermediates a) and b).

[0679] Light yellow oil (89.9%).

[0680] ISP-MS: m/e=288.2 (M+H⁺)

Examples 47 and 48

[0681](4R,9aR)-3,3,3-Trifluoro-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-(R)-propan-1-oland

[0682](4R,9aR)-3,3,3-Trifluoro-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-(S)-propan-1-ol

[0683] These compounds were prepared in analogy to Examples 39 and 40from(4R,9aR)-4-methyl-6-((RS)-3,3,3-trifluoro-1-hydroxy-propyl)-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester and subsequent separation of the diastereomers.

Example 47

[0684](4R,9aR)-3,3,3-Trifluoro-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-(R)-propan-1-ol

[0685] Light brown solid (50.9%).

[0686] ISP-MS: m/e=302.1 ([M+H⁺])

Example 48

[0687](4R,9aR)-3,3,3-Trifluoro-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-(S)-propan-1-ol

[0688] Colorless solid (36.4%).

[0689] ISP-MS: m/e=302.1 ([M+H⁺])

Intermediate

[0690](4R,9aR)-4-Methyl-6-((RS)-3,3,3-trifluoro-1-hydroxy-propyl)-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0691] This compound was prepared in analogy to Example 38 intermediate,from(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b), tert-butyllithium and3,3,3-trifluoropropanal.

[0692] Light brown oil (50.5%).

[0693] ISP-MS: m/e 402.4 ([M+H⁺])

Examples 49 and 50

[0694](4R,9aR)-(R)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-thiazol-2-yl-methanoland

[0695](4R,9aR)-(S)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-thiazol-2-yl-methanol

[0696] These compounds were prepared in analogy to Examples 39 and 40from(4R,9aR)-6-((RS)-hydroxy-thiazol-2-yl-methyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester and subsequent separation of the diastereomers.

Example 49

[0697](4R,9aR)-(R)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-thiazol-2-yl-methanol

[0698] Light yellow foam (29.6%).

[0699] ISP-MS: m/e=303.2 ([M+H⁺])

Example 50

[0700](4R,9aR)-(S)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-thiazol-2-yl-methanol

[0701] Light yellow foam (41.9%).

[0702] ISP-MS: m/e=303.2 ([M+H⁺])

Intermediate

[0703](4R,9aR)-6-((RS)-Hydroxy-thiazol-2-yl-methyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic.acid tert-butyl ester

[0704] This compound was prepared in analogy to Example 38 intermediate,from(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b), tert-butyllithium and2-thiazolecarboxaldehyde.

[0705] Colorless foam (82.3%).

[0706] ISP-MS: m/e=403.4 ([M+H⁺])

Example 51

[0707](4R,9aR)-2-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propan-2-ol

[0708] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(1-hydroxy-1-methyl-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.,

[0709] Light yellow oil (73.5%).

[0710] ISP-MS: m/e=248.3 ([M+H⁺])

Intermediate

[0711](4R,9aR)-6-(1-Hydroxy-1-methyl-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0712] A solution of 0.30 g (0.81 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 5 ml tetrahydrofuran was cooled to −78 deg C.and treated with 0.61 ml (0.98 mmol) n-butyllithium solution (1.6 M inn-hexane). After 30 min, 80 μL (71 mg, 1.22 mmol) acetone was added.After 30 min, the reaction was quenched with 10% aqueous ammoniumchloride and extracted with ethyl acetate. The organic layer was washedwith brine, dried over magnesium sulfate and filtered. The solvent wasremoved on a rotary evaporator and the residue was chromatographed onsilica gel (0.032-0.063 mm) with ethyl acetate: n-hexane (1: 1) aseluant to afford the compound as a light yellow foam (24.4%).

[0713] ISP-MS: m/e=348.5 ([M+H⁺])

Example 52

[0714](4R,9aR)-3-Methyl-2-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-butan-2-ol

[0715] This compound was prepared in analogy to Example 2,from(4R,9aR)-6-(1-(RS)-hydroxy-1,2-dimethyl-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0716] Light yellow oil (79.5%).

[0717] ISP-MS: m/e=276.2 ([M+H⁺])

Intermediate

[0718](4R,9aR)-6-(1-(RS)-Uydroxy-1,2-dimethyl-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0719] This compound was prepared in analogy to Example 51 intermediate,from(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b), n-butyllithium and3-methyl-2-butanone.

[0720] Colorless oil (39.8%).

[0721] ISP-MS: m/e=374.5 ([M+H⁺])

Example 53

[0722](4R,9aR)-1-Methoxy-2-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propan-2-ol

[0723] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(1-(RS)-hydroxy-2-methoxy1-methyl-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0724] Light yellow oil (84.6%).

[0725] ISP-MS: m/e=278.2 ([M+H⁺])

Intermediate

[0726](4R,9aR)-6-(1-(RS)-Hydroxy-2-methoxy-1-methyl-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0727] This compound was prepared in analogy to Example 5 1,intermediate, from(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b), n-butyllithium andmethoxy-2-propanone.

[0728] Colorless oil (46.5%).

[0729] ISP-MS: m/e=378.4 ([M+H⁺])

Example 54

[0730](4R,9aR)-5-Chloro-2-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-pentan-2-ol

[0731] This compound was prepared in analogy to Example 2 from(4R,9aR)-6-(4-chloro-1-(RS)-hydroxy-1-methyl-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0732] Colorless oil (77.8%).

[0733] ISP-MS: m/e=310.2 ([M+H⁺])

Intermediate

[0734](4R,9aR)-6-(4-Chloro-1-(RS)-hydroxy-1-methyl-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0735] A solution of 0.30 g (0.81 mmol)(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester in 20 ml diethyl ether was cooled to −100 deg C.and treated dropwise with 65 μl (0.97 mmol) tert-butyllithium (1.5 Msolution in n-pentane). Afterl5 min, 0.12 g (0.11 ml, 0.98 mmol)5-chloro-2-pentanone was added, the temperature was allowed to rise to−75 deg C. and after an additional 15 min, the reaction was quenchedwith 10%. aqueous ammonium chloride solution and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate and filtered. The solvent was removed on a rotary evaporator andthe residue was chromatographed on silica gel (0.032-0.063 mm) withethyl acetate :n-hexane (1:2) as eluant to afford the compound as acolorless oil (50.9%).

[0736] ISP-MS: m/e=410.4 ([M+H⁺])

Example 55

[0737](4R,9aR)4-Methyl-6-(2-(RS)-methyl-tetrahydro-furan-2-yl)-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0738] This compound was prepared in analogy to Example 2 from(4R,9aR)-4-methyl-6-(2-methyl-tetrahydro-furan-(RS)-2-yl)-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester.

[0739] Colorless oil (94.1%).

[0740] ISP-MS: m/e=274.2 ([M+H⁺])

Intermediate

[0741](4R,9aR)-4-Methyl-6-(2-methyl-tetrahydro-furan-(RS)-2-yl)-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0742] To a solution of 0.20 g (0.49 mmol)(4R,9aR)-6-(4-chloro-1-(RS)-hydroxy-1-methyl-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 49, intermediate) in 2.0 mlN,N-dimethylformamide was added 25.5 mg (0.59 mmol) sodium hydride(55-65% dispersion in oil). After 1 h the reaction mixture was pouredonto 10% aqueous ammonium chloride solution and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate and filtered. The solvent was removed on a rotary evaporator andthe residue was chromatographed on silica gel (0.032-0.063 mm) withethyl acetate: n-hexane (1:3) as eluant to afford the compound as acolorless oil (78.5%).

[0743] ISP-MS: m/e=347.5 ([M+H⁺])

Example 56

[0744](4R,9aR)-6-((RS)-1-Fluoro-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;di-trifluoroacetate

[0745] To a stirred solution of(4R,9aR)-6-(1-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (92 mg) in CH₂Cl₂ (3 ml) at 0° C. under argon wasadded DAST (73 μl). The solution was stirred for 1 hour and partitionedbetween CH₂Cl₂ and aqueous NaHCO₃. The phases were separated, theorganics washed with brine, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by column chromatography [SiO₂; isohexane-ethylacetate (4:1)]. The purified product was dissolved in CH₂Cl₂ (1 ml) andtrifluoroacetic acid (1 ml) was added. The solution was left to stand atroom temperature for 1 hour and concentrated in vacuo to afford(4R,9aR)-6-((RS)-1-fluoro-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorenedi-trifluoroacetate (50 mg) as a yellow oil: HPLC [Xterra; 50/80; 235nm] 97%, 0.71 min; MS (ES) 235.0 (MH⁺).

Intermediate

[0746](4R,9aR)-6-(1-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0747] To a stirred solution of(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) (2 g) in THF (24 ml)at −78° C. was added n-butyllithium (2.72 ml, 2.5 M in hexanes)dropwise. The solution was stirred at −78° C. for 45 mins andacetaldehyde (604 μl) in THF (2 ml) was added dropwise. The solution wasstirred for a further 2 hours, allowed to warm to room temperatureslowly and stirred for a further 4.5 hours. The reaction was quenchedwith aqueous ammonium chloride (20 ml), diluted with ethyl acetate andthe phases separated. The organics were washed successively with waterand brine, dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography [SiO₂; isohexane-ethyl acetate (3:2)]to afford(4R,9aR)-6-(1-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (742 mg) as a yellow oil: ¹H NMR (400 MHz, CDCl₃)7.16 (1H, d, J 7 Hz), 6.35 (1H, d, J 7 Hz), 4.37-4.31 (1H, br s),4.31-4.19 (1H, br s), 4.09-3.95 (1H, m), 3.95-3.85 (1H, m), 3.13-2.94(2H, m), 2.79-2.55 (1H, br s), 2.54 (1H, dd, J 6 and 16 Hz), 1.48 (9H,s), 1.44 (3H, d, J 6.5 Hz), 1.25 (1.5H, R epimer, d, J 6.5 Hz) and 1.24(1.5H, S epimer, d, J 6.5 HZ); MS (ES) 334.3 (MH⁺).

Example 57

[0748](4R,9aR)-6-((RS)-1-Fluoro-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0749](4R,9aR)-6-((RS)-1-Fluoro-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene(59 mg) was made from(4R,9aR)-6-(1-hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (52 mg) using the procedure described in Example56 to afford the product as a colorless oil: HPLC [Xterra; 20/50; 250nm] 100%, 2.17 min; MS (ES) 250.3 (MH⁺).

Intermediate

[0750](4R,9aR)-6-(1-Hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0751](4R,9aR)-6-(1-Hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (465 mg) was made from(4R,9aR)-6-bromo-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene(Example 5, intermediate b) (1 g), using propionaldehyde (390 μl) inplace of acetaldehyde, according to the procedure described in Example56, intermediate, to afford the product as a pale yellow solid (465 mg):¹H NMR (400 MHz, CDCl₃) 7.15 (1H, d, J 7 Hz), 6.33 (1H, d, J 7 Hz), 4.47(1H, t, J 5.5 Hz), 4.42-4.30 (1H, br s), 4.29-4.14 (1H, br s), 4.02-3.92(2H, m), 3.92-3.83 (1H, br s), 3.11-2.94 (2H, m), 2.81-2.58 (1H, br s),2.52 (1H, dd, J 6 and 16 Hz), 1.85-1.72 (1H, m), 1.72-1.56 (1H, m), 1.48(9H, s),1.24 (1.5H, epimer, 1, d, J 7 Hz), 1.23 (1.5H, epimer 2, d, J 7Hz), 0.95 (1.5H, epimer 1, t, J 7.5 Hz) and 0.94 (1.5H, epimer 2, t, J7.5 Hz); MS (ES) 348.0 (MH⁺).

Example 58

[0752](4R,9aR)-6-((RS)-1-Fluoro-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0753](4R,9aR)-6-((RS)-1-Fluoro-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorenedi-trifluoroacetate (47. mg) was made from6-(1-hydroxy-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (54 mg) according to the procedures described inExample 56 to afford the product as a colorless oil: HPLC [Xterra;50/80; 255 nm] 98.6%, 1.60 min; MS (ES) 264.0 (MH⁺).

Intermediate

[0754](4R,9aR)-6-(1-Hydroxy-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0755](4R,9aR)-6-(1-Hydroxy-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (430 mg) was made from(4R,9aR)-6-bromo-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene(Example 5, intermediate b) (1 g), using butyraldehyde (487 μl) in placeof acetaldehyde, according to the procedure described in Example 56,intermediate, to afford the product as an off-white solid (420 mg): ¹HNMR (400 MHz, CDCl₃) 7.14 (1H, d, J 7 Hz), 6.33 (1H, d, J 7 Hz),4.56-4.48 (1H, m), 4.40-4.29 (1H, br s), 4.26-4.13 (1H, br s), 4.03-3.93(2H, m), 3.93-3.86 (1H, br s), 3.11-2.92 (2H, m), 2.77-2.57 (1H, br s),2.51 (1H, dd, J 6 and 16 Hz), 1.77-1.58 (2H, m), 1.48 (9H, s), 1.48-1.39(2H, m), 1.24 (1.5H, epimer 1, d, J 7 Hz), 1.23 (1.5H, epimer 2, d, J 7Hz), 0.94 (1.5H, epimer 1, t, J 7.5 Hz) and 0.93 (1.5H, epimer 2, t, J7.5 Hz); MS (ES) 362.1 (MH⁺).

Example 59

[0756](4R,9aR)-6-Ethylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene

[0757](4R,9aR)-6-Ethylsulfanyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0758] THF (5 mL) was cooled to −78° C. under an argon atmosphere.n-Butyl lithium (1.6 M in hexanes, 0.5 mL, 0.8 mmol) was added and themixture was stirred at −78° C. for 5 min. A mixture of(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 5, intermediate b) (0.2 g, 0.54 mmol) inTHF (5 mL) was added dropwise, maintaining the temperature below −70 °C. The resultant dark red solution was stirred at −78° C. for 30 min andethyl disulfide (0.13 mL, 1.08 mmol) was added. The mixture was stirredat −78° C. for 2 h and left to warm to room temperature over 2 h. Water(1 mL) was added and the mixture was poured onto an isolute HM-N SPEcartridge and eluted with ethyl acetate (10 mL). The eluant wasevaporated under reduced pressure and the crude material was purified byreverse phase preparative HPLC (Prep Nova-Pak HR C18 6 μm 60Å30 mm×300mm column, UV detection at 254 nm, mobile phase 95:5 methanol: water and10 mmol ammonium acetate, gradient 50 methanol to 100% 0 to 10 min then100% methanol to 13 min, 20 mL/min) to afford the title compound (0.071g, 53 % yield) as a pale yellow oil: m/z 350.14 (MH⁺); HPLC (50% to 80%gradient [95:5 MeOH: water, 10 mmol ammonium acetate] 220 nm XTERRA 2.0ml/min) 6.21 min.(4R,9aR)-6-Ethylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene

[0759] A mixture of(4R,9aR)-6-ethylsulfanyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (0.02 g, 0.057 mmol), DCM (2 mL) and TFA (2 mL)was shaken at room temperature for 2 h. The reaction mixture wasevaporated under reduced pressure. The crude material was dissolved inmethanol and transferred onto a SCX-2 ion exchange column (500 mg) andwashed with methanol (10 mL), ammonia in methanol (2M, 3 mL) was addedand the eluant collected and evaporated under reduced pressure to affordthe title compound (0.014 g, 100% yield) as a pale yellow oil: m/z250.25 (MH⁺); HPLC (50% to 80% gradient [95:5 MeOH: water, 10 mmolammonium acetate] 220 nm XTERRA 2.0 ml/min) 1.23 min.

Example 60

[0760](4R,9aR)-6-Allylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene

[0761](4R,9aR)-6-Allylsulfanyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0762] This was prepared according to the method described in Example 59using allyl disulfide to produce 0.0578 g (30% yield) of the product asa pale yellow oil: m/z 462.16 (MH⁺); HPLC (50% to 80% gradient [95:5MeOH: water, 10 mmol ammonium acetate] 220 nm XTERRA 2.0 ml/min) 6.45min.

[0763](4R,9aR)-6-Allylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0764] This was prepared according to the method described in Example 59using(4R,9aR)-6-allylsulfanyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester to produce 0.014 g of the product as a pale yellowoil: m/z 262.19 (MH⁺); HPLC (50% to 80% gradient [95:5 MeOH: water, 10mmol ammonium acetate] 220 nm XTERRA 2.0 ml/min) 1.49 min.

Example 61

[0765](4R,9aR)-6-Propylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene

[0766](4R,9aR)-4-Methyl-6-propylsulfanyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0767] This was prepared according to the method described in Example 59using propyl disulfide to produce 0.053 g (27% yield) of the product asa pale yellow oil: m/z 364.24 (MH³⁰ ); HPLC (50% to 80% gradient [95:5MeOH: water, 10 mmol ammonium acetate] 220 nm XTERRA 2.0 ml/min) 6.94min.

[0768](4R,9aR)-6-Propylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0769] This was prepared according to the method described in Example 59from(4R,9aR)-4-methyl-6-propylsulfanyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester to produce 0.015 g of the product as a pale yellowoil: m/z 264.24 (MH⁺); HPLC (50% to 80% gradient [95:5 MeOH: water, 10mmol ammonium acetate] 220 nm XTERRA 2.0 ml/min) 2.02 min.

Example 62

[0770](4R,9aR)-6-Isopropylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene

[0771](4R,9aR)-6-Isopropylsulfanyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0772] This was prepared according to the method described in Example 59using isopropyl disulfide to produce 0.051 g (26% yield) of the productas a pale yellow oil: m/z 364.31 (MH⁺); NMR δ_(H) (400 MHz, CDCl₃) 1.25(3H, d, J 7.0 Hz), 1.36 (6H, d, J 6.5 Hz), 1.48 (9H, s), 2.55 (1H, dd, J16.5 and 6.0 Hz), 3.02-3.11 (4H, m), 3.84-4.02 (4H, m), 6.36 (1H, d, J7.0 Hz) and 7.0 (1H, d, J 7.0 Hz).

[0773](4R,9aR)-6-Isopropylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0774] This was prepared according to the method described in Example 59using(4R,9aR)-6-isopropylsulfanyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester to produce 0.0146 g of the product as a paleyellow oil: m/z 264.3 (MH⁺); NMR δ_(H) (400 MHz, CDCl₃) 1.37 (3H, d, J7.0 Hz), 1.39 (6H, d, J 7.0 Hz), 2.55 (1H, dd, J 16.0 and 5.5 Hz),2.69-3.15 (5H, m), 4.06-4.13 (1H, m), 4.46-4.50 (2H, m), 5.31 (1H, brs), 6.40 (1H, d, j 7.5 Hz) and 7.04 (1H, d, J 7.0 Hz).

Example 63

[0775](4R,9aR)-6-(1-(RS)-Methoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0776] To a solution of(4R,9aR)-6-(1-hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (52 mg) in DMF (1 ml) was added NaH (12 mg) underargon. The mixture was shaken at room temperature for 25 minutes, methyliodide (19 μl) was added and the mixture was shaken for a further 24hours. The mixture was partitioned between CH₂Cl₂ and aqueous NH₄Cl, thephases were separated and the dried organic layer was concentrated invacuo. The residue was purified by preparatory HPLC (Prep Nova-Pak HRC18 6 μm 60Å30 mm×300 mm column, UV detection at 254 nm, mobile phase95:5 methanol: water and 10 mmol ammonium acetate, gradient 50 methanolto 100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min). Thepurified product was deprotected according to the procedure describedfor Example 56 to afford(4R,9aR)-6-(1-(RS)-methoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorenedi-trifluoroacetate as a colorless oil (53 mg): HPLC [Xterra; 50/80; 255nm] 100%, 0.74 min; MS (ES) 262.1 (MH⁺).

Example 64

[0777](4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0778](4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorenedi-trifluoroacetate (32 mg) was made from6-(1-hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (52 mg), using cyclopropylmethyl bromide (29 μl)in place of methyl iodide, according to the procedures described inExample 63 to afford the product as a colorless oil. HPLC [Xterra;50/80; 255 nm] 100%, 1.44 min; MS (ES) 302.1 (MH⁺).

Example 65

[0779](4R,9aR)-6-(1-(RS)-Methoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0780](4R,9aR)-6-(1-(RS)-Methoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorenedi-trifluoroacetate (69 mg) was made from6-(1-hydroxy-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (54 mg), according to the procedure described inExample 63 to afford the product as a colorless oil: HPLC [Xterra;50/80; 255 nm] 99.8%, 1.05 min; MS (ES) 276.0 (MH⁺).

Example 66

[0781](4R,9aR)-6-(1-(RS)-Ethoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0782](4R,9aR)-6-(1-(RS)-Ethoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorenedi-trifluoroacetate (41 mg) was made from6-(1-hydroxy-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (54 mg), using ethyl iodide (21 μl) in place ofmethyl iodide, according to the procedures described in Example 63 toafford the product as a yellow oil: HPLC [Xterra; 50/80; 255 nm] 99.8%,1.46 min; MS (ES) 290.3 (MH⁺).

Example 67

[0783](4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene

[0784](4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorenedi-trifluoroacetate (53 mg) was made from6-(1-hydroxy-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (54 mg), using cyclopropylmethyl bromide (29 μl)in place of methyl iodide, according to the procedure described inExample 63 to afford the product as a colorless oil: HPLC [Xterra;50/80; 255 nm] 99.6%, 2.29 min; MS (ES) 316.4 (MH⁺).

Example 68

[0785] (4R,9aR)-Isopropyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene-6-ylmethylester(4R,9aR)-6-Isopropylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0786] A solution of(4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 15, intermediate b) (0.01 g, 0.03 mmol)and DCM (1 mL) was added to PS-BEMP (2.2 mmol/g, 0.03 g, 0.06 mmol). Themixture was shaken at room temperature for 5 min, isopropyl isocyanate(17 μL, 0.15 mmol) was added, the mixture was heated at 40° C. and leftto shake for 24 h. PS-Trisamine (4.7 mmol/g, 0.06 g, 0.3 mmol) and DCM(1 mL) were added and the reaction mixture was left to shake at roomtemperature for 4 h. The reaction mixture was filtered and the solidwashed with DCM (3 mL). The filtrate was evaporated and the crudeproduct purified by reverse phase preparative HPLC (Prep Nova-Pak HR C186 μm 60Å30 mm×300 mm column, UV detection at 254 nm, mobile phase 95:5methanol: water and 10 mmol ammonium acetate, gradient 50 methanol to100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min) to afford thetitle compound (0.053 g, 44% yield) as a pale yellow oil: m/z 405.29(MH⁺); NMR δ_(H) (400 MHz, CDCl₃) 1.15 (6H, d, J 6.5 Hz), 1.24 (3H, d, J6.5 Hz), 1.47 (9H, s) 2.50-2.60 (2H, m), 3.0-3.1 (2H, m), 3.8-3.9 (1H,m), 3.9-4.1 (2H, m), 4.5-4.6 (2H, m), 4.7-4.8 (1H, br s), 5.04 (2H, s),6.50 (1H, d,J7.0 Hz) and 7.18 (1H, d,J7.0 Hz).

[0787] (4R,9aR)-Isopropyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene-6-ylmethylester

[0788] This was prepared according to the method described in Example 59using(4R,9aR)-6-isopropylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H--2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester to produce 0.0033 g of the product as a paleyellow oil: m/z 305.33 (MH⁺); NMR δ_(H) (400 MHz, CDCl₃) 1.15 (6H, d, J6.5 Hz), 1.33 (3H, d, J 7.0 Hz), 2.46 (1H, dd, J 16.0 and 6.5 Hz), 2.62(1H, t, J 11.5 Hz), 2.84 (1H, d, J 12.0 Hz), 2.95-3.01 (2H, m), 3.05(1H, dd, J 12.0 and 3.5 Hz), 3.79-3.88 (1H, m), 3.95-4.02 (1H, m),4.35-4.39 (1H, m), 4.59 (1H, br s), 4.98 (2H, s), 6.44 (1H, d, J 7.0 Hz)and 7.11 (1H, d, J 7.0 Hz) (note NH unobserved).

Example 69

[0789] (4R,9aR)-tert-Butyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0790](4R,9aR)-6-tert-Butylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0791] This was prepared according to the method described in Example 68using tert-butyl isocyanate to produce 0.0061 g (49% yield) of theproduct as a pale yellow oil: m/z 419.28 (MH⁺); NMR δ_(H) (400 MHz,CDCl₃) 1.24 (3H, d, J7.0 Hz), 1.32 (9H, s), 1.47 (9H, s), 2.52-2.57 (4H,m), 3.01-3.08 (2H, m), 3.99-4.05 (2H, m), 4.50 (1H, br s), 4.98 (2H, s),6.47 (1H, d, J 7.0 Hz) and 7.17 (1H, d, J 7.0 Hz).

[0792] (4R,9aR)-tert-Butyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0793] This was prepared according to the method described in Example 59using(4R,9aR)-6-tert-butylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester to produce 0.003 g of the product as a pale yellowoil: m/z 319.32 (MH⁺); NMR δ_(H) (400 MHz, CDCl₃) 3.31 (3H, d, J 7.0Hz), 3.32 (9H, s), 2.45 (1H, dd, J 16.0 and 6.0 Hz), 2.61 (1H, t, J 12.0Hz), 2.80 (1H, d, J 12.0 Hz), 2.94 (1H, m), 3.01 (1H, dd, J 11.5 and 3.5Hz), 3.91-3.98 (2H, m), 4.34-4.36 (2H, m), 4.74 (1H, br s), 4.94 (2H,s), 6.41 (1H, d, J 7.0 Hz) and 7.1 (1H, d, J 7.0 Hz).

Example 70

[0794] Cyclohexyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0795](4R,9aR)-6-Cyclohexylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0796] This was prepared according to the method described in Example 68using cyclohexylisocyanate to produce 0.0058 g (44% yield) of theproduct as a pale yellow oil: m/z 445.28 (MH⁺); NMR δ_(H) (400 MHz,CDCl₃) 1.08 (6H, d, J 6.5 Hz), 1.23 (3H, d, J 7.0 Hz), 1.28 (6H, d, J7.5 Hz), 1.44 (9H, s), 2.60 (2H, m), 3.0-3.16 (2H, m), 3.84-4.0 (2H, m),4.44-4.96 (1H, m), 5.18 (2H, s), 6.48 (1H, d, J 7.0 Hz), 7.24 (1H, d, J7.0 Hz) and 8.25 (1H, br s).

[0797] Cyclohexyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0798] This was prepared according to the method described in Example 59using(4R,9aR)-6-cyclohexylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester to produce 0.0039g of the product as a pale yellowoil: m/z 345.31 (MH⁺); NMR δ_(H) (400 MHz, CDCl₃) 1.1-1.21 (6H, m), 1.31(3H, d, J 7.0 Hz), 1.56-1.61 (4H,m), 1.66-1.72 (2H, m), 1.91-1.96 (4H,m),2.45 (1H, dd, J 16.0 and 6.5 Hz), 2.60 (1H, t, J 11.0 Hz), 2.78 (1H,d, J 12.5 Hz), 2.93-2.97 (1H, m), 3.01 (1H, dd, J 12.0 and 3.5 Hz),3.49-3.54 (1H, m), 3.91-3.98 (1H, m), 4.31-4.37 (1H, m), 4.68 (1H, brs), 4.98 (2H, s), 6.42 (1H, d, J 7.0 Hz) and 7.10 (1H, d, J 7.0 Hz).

Example 71

[0799] (4R,9aR)-Ethyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0800](4R,9aR)-6-Ethylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0801] Ethyl isocyanate (22 mL, 0.31 mmol) was added to a mixture ofDMAP (0.008 g, 0.063 mmol)(4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (Example 15, intermediate b) (0.02 g, 0.063 mmol),4Å molecular sieves (0.02 g, crushed) and DCM (2 mL). The reactionvessel was sealed and heated at 140° C. in a CEM Discoverer™ microwavefor 15 min.

[0802] The reaction mixture was cooled to room temperature, DCM (2 mL)and AP-trisamine (2.49 mmol/g, 0.25 g, 0.63 mmol) were added, thereaction vessel was sealed and heated at 130° C. in a CEM Discoverer™microwave for 5 min. The reaction mixture was filtered and the solidwashed with DCM (4 mL) the filtrate was evaporated and the crude productpurified by reverse phase preparative HPLC (Prep Nova-Pak HR C18 6 μm60Å30 mm×300 mm column, UV detection at 254 nm, mobile phase 95:5methanol: water and 10 mmol ammonium acetate, gradient 50 methanol to100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min) to afford thetitle compound (0.053 g, 22% yield) as a pale yellow oil: m/z 391.28(MH⁺); HPLC (50% to 80% gradient [95:5 MeOH: water, 10 mmol ammoniumacetate] 255 nm XTERRA 2.0 ml/min) 2.98 min, 99%.

[0803] (4R,9aR)-Ethyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0804] This was prepared according to the method described in Example 59using(4R,9aR)-6-ethylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester to produce 0.001 Ig of the product as a paleyellow oil: m/z 291.28 (MH⁺); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammon ium acetate] 255 nm XTERRA 2.0 ml/min) 0.55 min,98.3 %.

Example 72

[0805] (4R,9aR)-Phenyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester(4R,9aR)-4-Methyl-6-phenylcarbamoyloxymethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0806] This was prepared according to the method described in Example 71using phenylisocyanate to afford 0.0106 g (38% yield) of the product asa pale yellow oil: m/z 439.28 (MH⁺); HPLC (50% to 80% gradient [95:5MeOH: water, 10 mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min) 5.76min, 82%.

[0807] (4R,9aR)-Phenyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0808] This was prepared according to the method described in Example 59using(4R,9aR)-4-methyl-6-phenylcarbamoyloxymethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester to produce 0.0023 g of the product, as a paleyellow oil: m/z 339.11 (MH⁺); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min) 1.33 min,99.2 %.

Example 73

[0809] (4R,9aR)-Benzyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0810](4R,9aR)-6-Benzylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0811] This was prepared according to the method described in Example 71using benzylisocyanate to produce 0.008 g (29% yield) of the product asa pale yellow oil: m/z 453.08 (MH⁺); HPLC (50% to 80% gradient [95:5MeOH: water, 10 mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min) 5.28min, 98.7 %.

[0812] (4R,9aR)-Benzyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0813] This was prepared according to the method described in Example 59using(4R,9aR)-6-benzylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester to produce 0.0023 g of the product as a paleyellow oil: m/z 353.30 (MH⁺); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min) 1.10 min,99.8%.

Example 74

[0814] (4R,9aR)-Allyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0815](4R,9aR)-6-Allylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0816] This was prepared according to the method described in Example 71using allylisocyanate to produce 0.0094 g (37% yield) of the product asa pale yellow oil: m/z 403.04 (MH⁺); HPLC (50% to 80% gradient [95:5MeOH: water, 10 mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min) 3.51min, 98%.

[0817] (4R,9aR)-Allyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0818] This was prepared according to the method described in Example 59using(4R,9aR)-6-allylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester to produce 0.0012 g of the product as a paleyellow oil: m/z 303.09 (MH⁺); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min) 0.60 min,96.3 %.

Example 75

[0819] (4R,9aR)-Ethyl-carbamic acid1-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propylester

[0820] To a solution of(4R,9aR)-6-(1-hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (52 mg) in THF (1 ml) was added NaH (12 mg). Themixture was shaken for 5 mins, ethylisocyanate was added and the mixtureshaken for 18 hours. The mixture was partitioned between CH₂Cl₂ andaqueous ammonium chloride, the phases were separated and the organicswere concentrated in vacuo. The residue was purified by preparatory HPLC(Prep Nova-Pak HR C18 6 μm 60Å30 mm×300 mm column, UV detection at 254nm, mobile phase 95 :5 methanol: water and 10 mmol ammonium acetate,gradient 50 methanol to 100% 0 to 10 min then 100% methanol to 13 min,20 mL/min). The purified product was deprotected according to the methoddescribed for Example 56 to afford (4R,9aR)-ethyl-carbamic acid1-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propylester di-trifluoroacetate (59 mg) as a colorless oil: HPLC [Xterra;50/80; 255 nm] 100%, 0.78 min; MS (ES) 319.2 (MH⁺).

[0821] Example 76

[0822] (4R,9aR)-Ethyl-carbamic acid1-(RS)-(4-methyl-1,23,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-butylester

[0823] (4R,9aR)-Ethyl-carbamic acid1-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-butylester di-trifluoroacetate (50 mg) was made from6-(1-hydroxy-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (54 mg), according to the procedure described inExample 75 to afford the product as a colorless oil: HPLC [Xterra;50/80; 255 nm] 100%, 1.09 min; MS (ES) 333.3 (MH⁺).

Example 77

[0824] (4R,9aR)-Ethyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester

[0825] (4R,9aR)-Ethyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester di-trifluoroacetate

[0826] (4R,9aR)-Ethyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester di-trifluoroacetate (50 mg) was made from6-(1S)-(1-hydroxy-ethyl)-(4R,9aR)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (40 mg) according to the procedure described inExample 75 to afford the product as a colorless oil: HPLC [Xterra;20/50; 250 nm] 99.5%, 1.90 min; MS (ES) 304.0 (MH⁺).

Example 78

[0827] (4R,9aR)-Propyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester di-trifluoroacetate

[0828] (4R,9aR)-Propyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester di-trifluoroacetate (55 mg) was made from6-((1S)-1-hydroxy-ethyl)-(4R,9aR)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (40 mg), using propylisocyanate (22 μl) in placeof ethylisocyanate, according to the procedure described in Example 75to afford the product as a colorless oil. HPLC [Xterra; 20/50; 250 nm]99.9%, 3.45 min; MS (ES) 318.0 (MH⁺).

Example 79

[0829] (4R,9aR)-Isopropyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester di-trifluoroacetate

[0830] (4R,9aR)-Isopropyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester di-trifluoroacetate (58 mg) was made from6-(1S)-(1-hydroxy-ethyl)-(4R,9aR)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (40 mg), using isopropylisocyanate (24 μl) inplace of ethylisocyanate, according to the procedure described inExample 75 to afford the product as a colorless oil. HPLC [Xterra;20/50; 255 nm] 100%, 3.17 min; MS (ES) 318.4 (MH⁺).

Example 80

[0831] (4R,9aR)-Pyrrolidine-1-carboxylic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0832](4R,9aR)-4-Methyl-6-(pyrrolidine-1-carbonyloxymethyl)-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester

[0833] A mixture of6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester (0.02 g, 0.063 mmol) and DCM (1 mL) was cooled to0° C. and carbonyl diimidazole (0.010 g, 0.063 mmol) was added, themixture was stirred at 0° C. for 2 h and stirred at room temperature for3 h. A mixture of pyrrolidine (10 mL, 0.13 mmol) and DCM (1 mL) wasadded and the reaction mixture was sealed and shaken at 60° C. for 48 h.The reaction mixture was cooled and water (2 mL) added, the mixture wasshaken at room temperature for 1 h then filtered through a PTFE frit.The filtrate was evaporated and the crude product purified by reversephase preparative HPLC (Prep Nova-Pak HR C18 6 μm 60Å30 mm×300 mmcolumn, UV detection at 254 nm, mobile phase 95:5 methanol: water and 10mmol ammonium acetate, gradient 50 methanol to 100% 0 to 10 min then100% methanol to 13 min) to afford the title compound (0.16 g, 61%yield) as a pale yellow oil: m/z 417.07 (MH⁺); HPLC (50% to 80% gradient[95:5 MeOH: water, 10 mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min)4.20 min, 99.3%.

[0834] (4R,9aR)-Pyrrolidine-1-carboxylic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0835] This was prepared according to the method described in Example 59using(4R,9aR)-4-methyl-6-(pyrrolidine-1-carbonyloxymethyl)-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester to produce 0.0018g of the product as a pale yellowoil: m/z 317.21 (MH⁺); HPLC (50% to 80% gradient [95:5 MeOH: water, 10mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min) 0.76 min, 100%.

Example 81

[0836] (4R,9aR)-Piperazine-1,4-dicarboxylic acid benzyl ester4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester(4R,9aR)-Piperazine-1,4-dicarboxylic acid benzyl ester2-tert-butoxycarbonyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethylester

[0837] This was prepared according to the method described in Example 80using piperazine-1-carboxylic acid benzyl ester to produce 0.0143g (40%yield) of the product as a pale yellow oil: m/z 566.30 (MH⁺); HPLC (50%to 80% gradient [95:5 MeOH: water, 10 mmol ammonium acetate] 255 nmXTERRA 2.0 ml/min) 6.03 min, 99.6%.

[0838] (4R,9aR)-Piperazine-1,4-dicarboxylic acid benzyl ester4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester

[0839] This was prepared according to the method described in Example 59using (4R,9aR)-piperazine-1,4-dicarboxylic acid benzyl ester2-tert-butoxycarbonyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethylester to produce 0.0035g (31% yield) of the product as a pale yellowoil: m/z 466.26 (MH⁺); HPLC (50% to 80% gradient [95:5 MeOH: water, 10mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min) 1.93 min, 95.6%.

Example A

[0840] Tablets containing the following ingredients can be manufacturedin a conventional manner: Ingredients Per tablet Compound of formula I10.0-100.0 mg Lactose 125.0 mg Maize starch 75.0 mg Talc 4.0 mgMagnesium stearate 1.0 mg

Example B

[0841] Capsules containing the following ingredients can be manufacturedin a conventional manner: Ingredients Per capsule Compound of formula I 25.0 mg Lactose 150.0 mg Maize starch  20.0 mg Talc  5.0 mg

Example C

[0842] Injection solutions can have the following composition: Compoundof formula I 3.0 mg Gelatin 150.0 mg Phenol 4.7 mg Water for ad 1.0 mlinjection solutions

What is claimed is:
 1. A compound of formula (I)

wherein R¹ is hydrogen, halogen, alkyl, cycloalkyl, alkenyl,alkoxycarbonylalkenyl, alkoxy, alkoxyalkyl, arylalkoxy, hydroxyalkyl,cyano, cycloalkylalkoxyalkyl, alkoxyalkoxyalkyl, arylalkoxyalkyl, amino,haloalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl,alkylcarbonyl, haloalkylcarbonyl, alkyl-S-, alkenyl-S-, A¹ or A²; R² ishydrogen, alkyl or alkoxy; R³ is alkyl, hydroxyalkyl or alkoxyalkyl; R⁴is hydrogen or alkyl; A¹ is

R^(a) is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl; R^(b) ishydrogen or alkyl; or R^(a) and R^(b) together with the oxygen atom andthe carbon atom to which they are attached form tetrahydrofuranyl; R^(C)is haloalkyl, alkyl, alkoxyalkyl or thiazolyl; A² is

R^(d) is alkyl, cycloalkyl, aryl, aralkyl or alkenyl; R^(e) is hydrogenor alkyl; or R^(d) and R^(e) together with the nitrogen atom to whichthey are attached form pyrrolidinyl or benzyloxycarbonylpiperazinyl;R^(f) is hydrogen or alkyl; R^(g) is hydrogen or alkyl; or thepharmaceutically acceptable salts, solvates and esters of said compound.2. The compound of claim 1, wherein R¹ is hydrogen, halogen, alkyl,cycloalkyl, alkenyl, alkoxycarbonylalkenyl, alkoxy, alkoxyalkyl,arylalkoxy, hydroxyalkyl, cyano, cycloalkylalkoxyalkyl,alkoxyalkoxyalkyl, arylalkoxyalkyl, amino or haloalkyl.
 3. The compoundof claim 2, wherein R² is hydrogen.
 4. The compound of claim 2, whereinR² is methyl.
 5. The compound of claim 4, wherein R³ is methyl.
 6. Thecompound of claim 5, wherein R⁴ is hydrogen.
 7. The compound of claim 2,wherein R¹ is hydrogen, halogen, alkyl, cycloalkyl,alkoxycarbonylalkenyl, alkoxyalkyl, cyano, cycloalkylalkoxyalkyl,alkoxyalkoxyalkyl, amino or haloalkyl.
 8. The compound according toclaim 7, wherein R¹ is hydrogen, chloro, bromo, methyl, ethyl,trifluoromethyl, cyclopropyl, ethoxycarbonylethenyl, methoxypropyl,cyano, cyclopropylmethoxymethyl, methoxyethoxymethyl, methoxymethyl orprimary amino.
 9. The compound of claim 8, wherein R¹ is fluoromethyl,difluoromethyl, hydroxy-ethyl, methoxyethyl, ethoxyethyl,cyclopropylmethoxy-ethyl or allyl-S-.
 10. A compound of formula (Ia)

wherein R¹ is hydrogen, halogen, alkyl, cycloalkyl, alkenyl,alkoxycarbonylalkenyl, alkoxy, alkoxyalkyl, arylalkoxy, hydroxyalkyl,cyano, cycloalkylalkoxyalkyl, alkoxyalkoxyalkyl, arylalkoxyalkyl, amino,haloalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl,alkylcarbonyl, haloalkylcarbonyl, alkyl-S-, alkenyl-S-, A¹ or A²; R² ishydrogen, alkyl or alkoxy; R³ is alkyl, hydroxyalkyl or alkoxyalkyl; R⁴is hydrogen or alkyl; A¹ is

R^(a) is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl; R^(b) ishydrogen or alkyl; or R^(a) and R^(b) together with the oxygen atom andthe carbon atom to which they are attached form tetrahydrofuranyl; R^(C)is haloalkyl, alkyl, alkoxyalkyl or thiazolyl;. A² is

R^(d) is alkyl, cycloalkyl, aryl, aralkyl or alkenyl; R^(e) is hydrogenor alkyl; or R^(d) and R^(e) together with the nitrogen atom to whichthey are attached form pyrrolidinyl or benzyloxycarbonylpiperazinyl;R^(f) is hydrogen or alkyl; R^(g) is hydrogen or alkyl; or thepharmaceutically acceptable salts, solvates and esters of said compound.11. A compound of formula (Ib)

wherein R¹ is hydrogen, halogen, alkyl, cycloalkyl, alkenyl,alkoxycarbonylalkenyl, alkoxy, alkoxyalkyl, arylalkoxy, hydroxyalkyl,cyano, cycloalkylalkoxyalkyl, alkoxyalkoxyalkyl, arylalkoxyalkyl, amino,haloalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl,alkylcarbonyl, halo alkylcarbonyl, alkyl-S-, alkenyl-S-, A¹ or A²; R² ishydrogen, alkyl or alkoxy; R³ is alkyl, hydroxyalkyl or alkoxyalkyl; R⁴is hydrogen or alkyl; A¹ is

R^(a) is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl; R^(b) ishydrogen or alkyl; or R^(a) and R^(b) together with the oxygen atom andthe carbon atom to which they are attached form tetrahydrofuranyl; R^(c)is haloalkyl, alkyl, alkoxyalkyl or thiazolyl; A² is

R^(d) is alkyl, cycloalkyl, aryl, aralkyl or alkenyl; R^(e) is hydrogenor alkyl; or R^(d) and R^(e) together with the nitrogen atom to whichthey are attached form pyrrolidinyl or benzyloxycarbonylpiperazinyl;R^(f) is hydrogen or alkyl; R^(g) is hydrogen or alkyl; or thepharmaceutically acceptable salts, solvates and esters of said compound.12. A compound selected from the group(R)-6-Chloro-4-methyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-Chloro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aS)-6-Chloro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(R)-6-Bromo-4-methyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-Bromo-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aS)-6-Bromo-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(R)-4,6-Dimethyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;(4R,9aR)-4,6-Dimethyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-Ethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;and(4R,9aR)-4-Methyl-6-trifluoromethyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene.13. A compound selected from the group(4R,9aR)-6-Cyclopropy1-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-3-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-acrylicacid ethyl ester;(4R,9aR)-6-(3-Methoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene-6-carbonitrile;(4R,9aR)-6-Cyclopropylmethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-(2-Methoxy-ethoxymethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-Methoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(R)-4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylamine;(R)-6-Chloro-4,9-dimethyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene; and(4R,9aR)-6-Benzyloxy-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene.14. A compound selected from the group(4R,9aR)-6-Methoxy-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-Ethoxy-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-2-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yloxy)-ethanol;(4R,9aR)-6-(2-Methoxy-ethoxy)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-Cyclobutylmethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-Ethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-Cyclohexylmethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-2-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethoxy)-ethanol;(4R,9aR)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-methanol;(4R,9aR)-6-Isobutyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;and(4R,9aR)-6-Difluoromethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene.15. A compound selected from the group(4R,9aR)-6-Fluoromethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-1(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethanone;(4R,9aR)-1-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propan-1-one;(4R,9aR)-1-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-butan-1-one;(4R,9aR)-2,2,2-Trifluoro-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethanone;(4R,9aR)-1-(RS)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethanol;(4R,9aR)-6-(1-(R)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(S)-Hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene;and(4R,9aR)-6-(1-(R)-Methoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene.16. A compound selected from the group(4R,9aR)-6-(1-(S)-Methoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(R)-EthQxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(R)-Cyclopropylmethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(S)-Ethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(S)-Cyclopropylmethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-3,3,3-Trifluoro-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-(R)-propan-1-ol;(4R,9aR)-3,3,3-Trifluoro-1-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-(S)-propan-1-ol;(4R,9aR)-(R)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-thiazol-2-yl-methanol;(4R,9aR)-(S)-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-thiazol-2-yl-methanol;and(4R,9aR)-2-(4-Methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propan-2-ol.17. A compound selected from the group(4R,9aR)-3-Methyl-2-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-butan-2-ol;(4R,9aR)-4-Methoxy-2-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propan-2-ol;(4R,9aR)-5-Chloro-2-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-pentan-²-ol;(4R,9aR)4-Methyl-6-(2-(RS)-methyl-tetrahydro-furan-2-yl)-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-((RS)-1-Fluoro-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-((RS)-1-Fluoro-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-((RS)-1-Fluoro-.butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-Ethylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene;(4R,9aR)-6-Allylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene;(4R,9aR)-6-Propylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene;and(4R,9aR)-6-Isopropylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene.18. A compound selected from the group(4R,9aR)-6-(1-(RS)-Methoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-propyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(RS)-Methoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(RS)-Ethoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-Isopropyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene-6-ylmethylester;(4R,9aR)-tert-Butyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;Cyclohexyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;(4R,9aR)-Ethyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;(4R,9aR)-Phenyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;and (4R,9aR)-Benzyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester.19. A compound selected from the group (4R,9aR)-Allyl-carbamic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;(4R,9aR)-Ethyl-carbamic acid1-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-propylester; (4R,9aR)-Ethyl-carbamic acid1-(RS)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-butylester; (4R,9aR)-Ethyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester; (4R,9aR)-Propyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester; (4R,9aR)-Isopropyl-carbamic acid1-(S)-(4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-yl)-ethylester; (4R,9aR)-Pyrrolidine-1-carboxylic acid4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester;and (4R,9aR)-Piperazine-1,4-dicarboxylic acid benzyl ester4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluoren-6-ylmethyl ester.20. A compound selected from the group:(4R,9aR)-6-chloro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-bromo-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(R)-4,6-dimethyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;(4R,9aR)-4,6-dimethyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-ethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-4-methyl-6-trifluoromethyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-cyclopropyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;and(4R,9aR)-6-cyclopropylmethoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene.21. A compound selected from the group:(4R,9aR)-6-methoxymethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(R)-6-chloro-4,9-dimethyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-difluoromethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-fluoromethyl-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)L6-(1-(S)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(S)-methoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(S)-ethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;(4R,9aR)-6-(1-(S)-cyclopropylmethoxy-ethyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene;and(4R,9aR)-6-allylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene.22. A process for preparing a compound of formula I, claim 1,comprising: a) reducing a compound of formula B to obtain a compound offormula Ib

wherein R¹ to R³ are defined as in claim 1, R⁴ is hydrogen and R^(a) isalkyl.
 23. A process for preparing a compound of formula I, claim 1,comprising reducing a compound of formula D to obtain a compound offormula Ib

wherein R¹ to R³ are defined as in claim 1 and R⁴ is hydrogen.
 24. Aprocess for preparing a compound of formula I, claim 1, comprisingreducing a compound of formula Ib to obtain a compound of formula Ia

wherein R¹ to R⁴ are defined as in claim
 1. 25. A process for preparinga compound of formula I, claim 1, comprising reducing a compound offormula K to obtain a compound of formula Ia

wherein R¹ to R⁴ are defined as in claim
 1. 26. A process for preparinga compound of formula I, claim 1, comprising cleaving the protectivegroup (PG) of a compound of formula Ic to obtain a compound of formulaId

wherein R¹ to R³ are defined as in claim
 1. 27. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula I, claim 1, and a therapeutically inert carrier.
 28. A methodfor the treatment of illnesses that are caused by disorders associatedwith the 5-HT₂ receptors comprising administering to a patient in needof such therapy a therapeutically effective amount of a compound offormula I, claim
 1. 29. A method for the treatment and prophylaxis ofeating disorders comprising administering to a patient in need of suchtherapy a therapeutically effective amount of a compound of formula I,claim
 1. 30. A method of treating obesity comprising administering to apatient in need of such therapy a therapeutically effective amount of acompound of formula I, claim
 1. 31. A method of treating diabetesmellitus, Type I diabetes, Type II diabetes, diabetes secondary topancreatic disease, diabetes related to steroid use, Type III diabetes,hyperglycaemia, diabetic complications and insulin resistance comprisingadministering to a patient in need of such therapy a therapeuticallyeffective amount of a compound of formula I, claim
 1. 32. A method oftreating Type II diabetes comprising administering to a patient in needof such therapy a therapeutically effective amount of a compound offormula I, claim
 1. 33. A method of treating disorders of the centralnervous system are selected from depression, atypical depression,bipolar disorders, anxiety disorders, obsessive-compulsive disorders,social phobias or panic states, sleep disorders, sexual dysfunction,psychoses, schizophrenia, migraine and other conditions associated withcephalic pain or other pain, raised intracranial pressure, epilepsy,personality disorders, age-related behavioural disorders, behaviouraldisorders associated with dementia, organic mental disorders, mentaldisorders in childhood, aggressivity, age-related memory disorders,chronic fatigue syndrome, drug and alcohol addiction, bulimia, anorexianervosa, premenstrual tension, trauma, stroke, neurodegenerativediseases, encephalitis and meningitis comprising administering to apatient in need of such therapy a therapeutically effective amount of acompound of formula I, claim
 1. 34. A method of treatment of obesity ina human in need of such treatment comprising administration to the humana therapeutically effective amount of a compound of claim 1 and atherapeutically effective amount of a lipase inhibitor.
 35. The methodof claim 34, wherein the lipase inhibitor is orlistat.
 36. The method ofclaim 35 wherein the compound of formula I and the lipase inhibitor areadministered simultaneously, separately or sequentially.
 37. Thepharmaceutical composition of claim 27 further comprising atherapeutically effective amount of a lipase inhibitor.
 38. Thepharmaceutical composition of claim 37, wherein the lipase inhibitor isorlistat.
 39. A compound selected from the group consisting of:(4R,10aR)-6-Bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylicacid tert-butyl ester; 7-Oxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylicacid 1-tert-butyl ester 2-ethyl ester; 6-Bromo-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester;6-Bromo-1H-pyrrolo [2,3-b]pyridine-2-carboxylic acid ethyl ester;6-Hydroxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester; and6-Hydroxy-pyrrolo [2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester.